KR20180055634A - Method for screening metastasis inhibitor for cancer - Google Patents
Method for screening metastasis inhibitor for cancer Download PDFInfo
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- KR20180055634A KR20180055634A KR1020170019666A KR20170019666A KR20180055634A KR 20180055634 A KR20180055634 A KR 20180055634A KR 1020170019666 A KR1020170019666 A KR 1020170019666A KR 20170019666 A KR20170019666 A KR 20170019666A KR 20180055634 A KR20180055634 A KR 20180055634A
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- cancer
- hyaluronic acid
- leu
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Abstract
Description
본 발명은 암 전이 억제제의 스크리닝 방법과 암의 전이 가능성의 예측에 대한 정보를 제공하는 방법에 관한 것으로, 보다 상세하게는 뇌암 전이 억제제의 스크리닝 방법과 뇌암의 전이 가능성의 예측에 대한 정보를 제공하는 방법에 관한 것이다.The present invention relates to a screening method of cancer metastasis inhibitor and a method of providing information on the prediction of cancer metastasis potential, and more particularly, to a screening method of brain metastasis inhibitor and information on prediction of metastatic potential of brain metastasis ≪ / RTI >
교모세포종(glioblastoma, GBM)은 성인 뇌암 중에서 가장 흔하지만 치명적인 뇌암에 속한다. 최근의 외래적 또는 의료적 치료에도 불구하고, 교모세포종은 여전히 치료율이 매우 낮다. 그 원인으로는 뇌 실질(parenchyma)로 교모세포종 세포의 침윤성에 해당하며, 상기한 침윤 과정에서 교모세포종은 다양한 세포외 기질(extracellular matrix, ECM) 분자와 상호작용을 수행한다. Glioblastoma (GBM) is the most common but fatal brain cancer among adult brain cancer. Despite recent outpatient or medical treatments, glioblastomas still have a very low rate of cure. The cause is the parenchyma, which corresponds to invasiveness of glioblastoma cells. In the process of invasion, glioblastomas interact with various extracellular matrix (ECM) molecules.
간엽 줄기 유사세포(Mesenchymal stem like cells)는 다능성(multipotent) 미분화 세포로서 다양한 형태의 세포로 분화할 수 있다. 이러한 특징으로 세포 치료제로서의 가능성을 갖고 많은 연구가 진행되고 있는 실정이다. 하지만 암과의 상호작용을 통한 그 역할은 밝혀지지 않은 상태이다.Mesenchymal stem like cells are multipotent undifferentiated cells and can differentiate into various types of cells. Many of these studies have been carried out with the potential of being a cell therapy agent. However, its role through interaction with cancer is unknown.
신체는 방어체계를 제어하고 자극하는 신호물질(분비인자)을 통하여 선천성 면역반응 및 적응 면역반응을 일으킨다. 이러한 분비인자들은 당단백질이며, 펩타이드 중 하나이다. 분비인자는 많은 종류의 세포에서 방출되며 신경전달물질 및 호르몬과 유사한 화학적 신호를 보내기도 한다. 각 분비인자들은 세포 표면의 특이적 수용기에 결합할 수 있으며, 세포 내의 신호를 전달함으로써 세포 기능을 바꾸는 역할을 한다. 보통 분비 인자는 면역반응에 관여를 한다고 알려져 있지만, 실질적으로 암 세포에 영향을 줄 수 있다는 보고가 최근 급격히 밝혀지고 있는 추세이다.The body causes congenital and adaptive immune responses through signaling substances (secretory factors) that control and stimulate the defense system. These secretion factors are glycoproteins and are one of the peptides. Secretion factors are released from many kinds of cells and they send chemical signals similar to neurotransmitters and hormones. Each secretion factor binds to specific receptors on the cell surface and plays a role in altering cell function by transmitting signals in the cell. Although the secretory factor is known to be involved in the immune response, there is a growing trend to report that it can actually affect cancer cells.
최근 Friedl P et al., Cancer invasion and the microenvironment: plasticity and reciprocity. Cell. 147(5):992-1009(2011)에 세포 외 기질 및 종양 조직에 혼재된 스트로마 세포, 마이엘로이드 세포 및 혈관 형성 세포 등의 다양한 세포 유형들은 종양 증식, 침윤, 이동 및 전이 등의 각 단계에 특이적인 종양 미세 환경 형성을 위하여 서로 다르게 다양한 영향을 미칠 것으로 예측되어 사이토카인을 위주로 하는 몇몇 분비인자들의 역할이 밝혀졌지만, 이들 세포 유형 각각의 악성화 단계 특이적인 미세 환경 형성 조절 기전 및 악성화 단계 특이적인 미세 환경 형성을 위한 암 줄기세포 또는 암 세포와 미세 환경 형성 세포간의 상호작용 기전은 구체적으로 규명되지 않고 있다. 또한, Mesenchymal stem cells in health and disease. NatRevImmunol. 8(9):726-36, Inflammation joins the "niche". CancerCell. 14(5):347-9 및 Deadly teamwork: neural cancer stem cells and the tumor microenvironment. CellStemCell. 8(5):482-5 등의 논문을 통하여 면역 염증세포, 스트로마 세포, 혈관 형성 세포, 간엽 세포(mesenchymal cells) 및 암 줄기세포로부터 분화된 다양한 종류의 암세포 등과의 상호작용으로 암 줄기세포 특이적인 미세 환경 (Niche)을 유지하는데, 이들 미세 환경 형성 세포들은 성장인자(growth factors)나 사이토카인(cytokine)을 포함하는 다양한 인자들을 분비하거나 혈관 신생을 유도하기도 하여 암 줄기세포가 생존하고 증식하기 적합한 환경을 제공한다고 알려져 있다.Recently, Friedl P et al., Cancer invasion and microenvironment: plasticity and reciprocity. Cell. Various cell types such as stromal cells, myeloid cells, and angiogenic cells mixed with extracellular matrix and tumor tissue at 147 (5): 992-1009 (2011) are used for each step such as tumor proliferation, invasion, migration and metastasis . The role of several cytokine-specific secretory factors has been elucidated. However, the specific mechanism of microenvironmental regulation and the specificity of the malignant stage The mechanism of interaction between cancer stem cells or cancer cells and microenvironmental cells for the formation of microenvironment has not been elucidated. In addition, Mesenchymal stem cells in health and disease. NatRevImmunol. 8 (9): 726-36, Inflammation joins the "niche". CancerCell. 14 (5): 347-9 and Deadly teamwork: neural cancer stem cells and the tumor microenvironment. CellStemCell. 8 (5): 482-5, etc., through interaction with various kinds of cancer cells differentiated from immune inflammatory cells, stromal cells, angiogenic cells, mesenchymal cells and cancer stem cells, These micro-environment-forming cells secrete various factors including growth factors and cytokines, induce angiogenesis, and survive and proliferate cancer stem cells. It is known to provide a suitable environment.
종래의 암 치료방법은 암 세포 자체의 신호 기작과 분비 물질에 대하여 초점이 맞추어져 실험이 진행되고 있었다. 또한, 그러한 결과들로 현재 사용되고 있는 항암제의 대부분은 암 세포의 신호 또는 암 세포의 특성을 표적으로 하는 경우가 많다. 하지만 이러한 치료 방법에도 불구하고, 암은 쉽게 치료되지 못하고 재발이 일어나고 있으며 다른 부위로의 전이가 일어나고 있어 보다 본질적인 치료방법이 요구됨에 따라 암의 악성화, 전이 및 재발의 원인으로 판단되는 암 세포의 주변 환경을 타겟으로 암을 치료하고자 하는 치료 프로토콜 개발에 관심이 높아지고 있다.Conventional cancer treatment methods have focused on the signaling mechanism and secretory substance of cancer cell itself and the experiment has been proceeding. In addition, as a result, many of the anticancer drugs currently in use often target the signal of cancer cells or the characteristics of cancer cells. However, in spite of these treatments, cancer is not easily treated and recurrence occurs, and metastasis to other parts is required. Therefore, the essential treatment method is required, so that the cancer cell is judged to be the cause of malignancy, metastasis and recurrence of cancer There is a growing interest in developing treatment protocols that target the environment to treat cancer.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
본 발명의 일 목적은 암-간엽 줄기 유사 세포(tumor mesenchymal stem-like cell, tMSLC)에 있어서 히알루론산 합성 효소 2(Hyaluronic acid synthase 2, HAS 2)의 발현 수준을 측정하여 뇌암 전이 억제제를 스크리닝 하는 방법을 제공하고자 한다. One object of the present invention is to screen the inhibitor of brain cancer metastasis by measuring the expression level of hyaluronic acid synthase 2 (HAS 2) in tumor mesenchymal stem-like cells (tMSLC) Method.
본 발명의 다른 목적은 암-간엽 줄기 유사 세포에서 히알루론산 합성 효소 1(Hyaluronic acid synthase 1, HAS 1), 히알루론산 합성 효소 2 및 히알루론산 합성 효소 3(Hyaluronic acid synthase 3, HAS 3)의 발현 수준을 측정하여 뇌암의 전이 가능성을 예측할 수 있는 정보를 제공하는 방법을 제공하고자 한다. A further object of the present invention is to provide a method for the expression of hyaluronic acid synthase 1 (HAS 1),
최근에 상기 암 진행 과정과 관련하여 상기 세포 외 기질에 대한 연구가 활발히 진행되고 있다. 세포 외 기질의 성분에 있어서, 다른 조직에 비하여 특히 뇌에는 히알루론산(hyaluronic acid, HA)이 풍부하게 분포하며, 교모세포종 세포의 침윤에 미세 환경을 제공하는 것으로 알려져 있다. 게다가, 상기 히알루론산은 주변의 정상적인 뇌 실질보다 뇌 종양에서 특히 많이 분포하고, 그 히알루론산이 많이 분포하는 교모세포종 환자의 경우 예후가 나쁠 것으로 예측하고 있다. Recently, the extracellular matrix has been actively studied in relation to the cancer progression. In the components of the extracellular matrix, hyaluronic acid (HA) is abundantly distributed in the brain, especially in the brain, as compared with other tissues, and it is known to provide a micro environment for the infiltration of glioblastoma cells. In addition, the above-mentioned hyaluronic acid is particularly distributed in cerebral tumors rather than the surrounding normal brain parenchyma, and it is predicted that the prognosis of glioblastoma patients having a large amount of hyaluronic acid is bad.
한편, 히알루론산은 음전하를 띠며, 글루쿠론산과 N-아세틸글루코사민으로 이루어지는 이당류가 반복되어 이루어지는 비분지 중합체에 해당한다. 정상적인 뇌조직에서, 상기 히알루론산은 1차 세포 외 기질의 구성 성분으로, 점성과 수분을 보유하는 성질로 인하여 조직 항상성이나 구조 등에 있어서 중요한 역할을 한다. On the other hand, hyaluronic acid is negatively charged and corresponds to an unbranched polymer in which disaccharides composed of glucuronic acid and N-acetylglucosamine are repeated. In normal brain tissue, hyaluronic acid is a component of the primary extracellular matrix, and plays an important role in tissue homeostasis and structure due to its viscosity and moisture retention properties.
종양을 포함하는 병리적 조건에 있어서, 히알루론산은 정상적인 조직에 비하여 손상 조직에서 풍부하게 분포하고, 뇌암에서 상기 히알루론산이 풍부하게 존재함으로써, CD44(cluster determinant 44), RHAMM(receptor for hyalunonate-mediated motility), 및 ICAM-1(intercellular adhesion molecule-1) 등과 같은 인지체 수용체(cognate receptors)를 통하여 세포간 신호 전달에서 리간드로 작용하거나, 기계적 보강(stiffening)을 제공하여 교모세포종 세포의 이동성을 증진시킨다. 이에 따라, 히알루론산의 함량은 종양 세포의 침윤성에 비례 관계에 있다. In pathological conditions involving tumors, hyaluronic acid is abundantly distributed in damaged tissues as compared to normal tissues, and due to the abundance of hyaluronic acid in brain cancer, CD44 (cluster determinant 44), receptor for hyalunonate-mediated motility, and cognate receptors such as intercellular adhesion molecule-1 (ICAM-1), or by providing mechanical stiffening to enhance the mobility of glioblastoma cells . Accordingly, the content of hyaluronic acid is proportional to the invasiveness of tumor cells.
하지만, 아직까지는 교모세포종의 침윤성과 관련된 기계적 및 세포 신호적 기능에 있어서 연구가 미흡한 편이며, 뇌암에서 히알루론산이 많이 분포하는 것과 관련하여 다양한 세포의 메커니즘에 대하여 아직 알려진 바 없다. However, studies on the mechanical and cell signaling functions related to invasiveness of glioblastomas are still insufficient, and the mechanism of various cells related to the distribution of hyaluronic acid in brain cancer is not yet known.
최근에 암-간엽 줄기 유사 세포(tumor-associated mesenchymal stem-like cells, tMSLCs)는 교모세포종 세포와 상호작용을 할 수 있는 기질 세포로, 암 진행에 있어서 잠재적인 역할에 대한 연구가 진행되고 있다. 하지만, 그 역할에 대하여 아직 충분히 알려지지 않았다. Recently, tumor-associated mesenchymal stem-like cells (tMSLCs) are stromal cells capable of interacting with glioblastoma cells, and their potential role in cancer progression is being studied. However, its role has not yet been fully understood.
본 발명의 발명자들은 침윤성 및 전이성이 높은 교모세포종의 경우, 상기 교모세포종에서 분리한 암-간엽 줄기 유사 세포(tumor mesenchymal stem-like cell, tMSLC)에서 히알루론산 합성 효소 2(Hyaluronic acid synthase 2, HAS 2)의 발현량이 교모세포종 세포에 비하여 두드러지게 높은 것을 발견하여 본 발명에 이르게 되었다. In the case of glioblastomas with high invasiveness and metastasis, the inventors of the present invention found that hyaluronic acid synthase 2 (HAS) was detected in tumor mesenchymal stem-like cells (tMSLC) 2) was markedly higher than that of glioblastoma cells, leading to the present invention.
본 발명의 일 구현 예에 따르면, (a) 암 환자로부터 암-간엽 줄기 유사 세포를 분리하는 단계; (b) 분리된 암-간엽 줄기 유사 세포에 약물을 처리하는 단계; (c) 상기 약물이 처리된 암-간엽 줄기 유사 세포의 히알루론산 합성 효소(Hyaluronic acid synthase, HAS) 또는 이를 코딩하는 mRNA의 발현 수준을 측정하는 단계; 및 (d) 상기 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 또는 이를 코딩하는 mRNA의 발현 수준이 약물 처리 전에 비하여 감소된 경우, 상기 약물을 암 전이 억제제 후보물질로 판단하는 단계를 포함하는 암 전이 억제제의 스크리닝 방법에 관한 것이다.According to one embodiment of the present invention, there is provided a method of treating cancer, comprising: (a) isolating cancer-stem cell-like cells from a cancer patient; (b) treating the drug with isolated cancer-mesenchymal stem cells; (c) measuring the expression level of hyaluronic acid synthase (HAS) of the cancer-mesenchymal stem cell-like cell treated with the drug or the mRNA encoding the same; And (d) judging the drug as a cancer metastasis inhibitor candidate when the expression level of the hyaluronic acid synthase or the mRNA coding therefor of the cancer stem cell-like cell is decreased as compared with that before the drug treatment, And a screening method of an inhibitor.
본 발명의 방법을 각각의 단계 별로 상세하게 설명하면 다음과 같다:The method of the present invention will be described in detail in each step as follows:
단계 (a): 암 환자로부터 암-간엽 줄기 유사 세포를 분리하는 단계에 해당한다. Step (a): isolating cancer-stem cell-like cells from cancer patients.
본 발명에서 상기 암 환자는, 신체 조직의 자율적인 과잉 성장에 의해 비정상적으로 자라난 덩어리인 암(cancer) 혹은 종양(tumor)의 질환이 있는 환자로서, 예를 들면, 뇌암, 폐암, 비소세포성폐암, 결장암, 골암, 췌장암, 피부암, 두부 또는 경부 암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS; central nervous system) 종양, 1차 CNS 림프종, 척수 종양, 및 뇌하수체 선종으로 이루어진 군에서 선택되는 암 질환이 있는 환자일 수 있으나, 바람직하게는 뇌암 환자일 수 있고, 보다 바람직하게는 교모세포종(glioblastoma) 환자일 수 있으며, 더욱 바람직하게는 침윤성 및 전이성이 높은 교모세포종 환자일 수 있다. In the present invention, the cancer patient is a patient suffering from a cancer or tumor disease which is abnormally grown by autonomous overgrowth of the body tissue, for example, brain cancer, lung cancer, non-small cell Cancer, ovarian cancer, rectum cancer, gastric cancer, anorectal cancer, colon cancer, breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, pancreatic carcinoma, Cancer of the prostate, chronic or acute leukemia, lymphocytic lymphoma, endometrioid cancer, endometrial carcinoma, thyroid cancer, pituitary cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, Cancer with a cancer selected from the group consisting of bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, and pituitary adenoma Giles number, but it may be preferably a brain tumor patient, may be more preferably glioblastoma patient (glioblastoma), may be more preferably glioblastoma patients with invasive and metastatic high.
단, 본 발명에서 상기 환자는 포유류에 해당하는 동물을 모두 포함할 수 있으나, 바람직하게는 인간일 수 있다.However, in the present invention, the patient may include all animals corresponding to mammals, but preferably it may be a human.
또한, 본 발명에서 상기 암-간엽 줄기 유사세포(tumor-associated mesenchymal stem-like cells, tMSLCs)는 제대혈과 골수에 존재하는 골 세포, 연골 세포, 근육 세포 및 섬유 세포 등 골격계 세포로 분화되는 줄기세포인 중간엽 줄기세포와 유사한 특징을 가진 세포를 의미한다. 상기 암-간엽 줄기 유사세포는 중간엽 줄기세포와 유사하게, ⅰ) 플라스틱 부착능을 갖고, ⅱ) 표면 항원 프로파일이 CD105+, CD90+, CD73+, CD45-, CD31- 및 NG2-을 나타내며, ⅲ) 지방 세포, 골 형성 및 연골 형성의 분화능을 보일 수 있다. In addition, in the present invention, the tumor-associated mesenchymal stem-like cells (tMSLCs) are stem cells differentiated into skeletal cells such as bone cells, cartilage cells, muscle cells and fibroblasts existing in cord blood and bone marrow Which is similar to mesenchymal stem cells. CD20 +, CD90 +, CD45-, CD31-, and NG2-, and iii) the adipose tissue of the adipocyte stem cells, wherein the cancer-mesenchymal stem cells are similar to mesenchymal stem cells, Cells, osteogenesis and cartilage formation.
본 발명에서 상기 암-간엽 줄기 유사세포는 암 조직, 바람직하게는 뇌암, 보다 바람직하게는 교모세포종, 더욱 바람직하게는 침윤성 또는 전이성이 높은 교모세포종으로부터 분리된 것일 수 있다. In the present invention, the cancer-mesenchymal stem cells may be isolated from cancer tissue, preferably brain cancer, more preferably glioblastoma, more preferably glioblastoma which is highly invasive or metastatic.
단계 (b): 분리된 암-간엽 줄기 유사 세포에 약물을 처리하는 단계에 해당한다.Step (b): treating the drug with isolated cancer-mesenchymal stem cells.
본 발명에서는 상기 암 환자로부터 분리된 암-간엽 줄기 유사 세포에 약물로 시험 물질을 처리할 수 있다. In the present invention, the test substance can be treated with a drug to cancer-mesenchymal stem cells isolated from the cancer patient.
다만, 본 발명에서는 상기 시험 물질과 함께 시너지 효과를 얻기 위하여 항암제를 함께 처리할 수 있다. 여기서 상기 항암제로는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상을 사용할 수 있으나, 이에 제한되는 것은 아니다. However, in the present invention, an anticancer agent may be treated together with the test substance to obtain a synergistic effect. Examples of the anticancer agent include nitrogene mustard, imatinib, oxaliplatin, rituximab, elotinib, neratinib, lapatinib, zetitib, bandetanib, nilotinib, semathanib, conservinib, acitinib, Corticosteroids, cisplatin, cetuximab, bismuth alum, asparaginase, tretinoin, hydroxycarbamides, corticosteroids, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, Amlodipine, amitriptyline, amitriptyline, amitriptyline, amlodipine, amlodipine, amlodipine, amlodipine, amlodipine, amlodipine, But are not limited to, but are not limited to, tamavir, tamifluuridine, femetrexed, tegafur, capecitabine, gimeracin, oteracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, Tamide, decitabine, Wherein the compound is selected from the group consisting of mercaptopurine, thioguanine, cladribine, calmophor, ralitriptycde, docetaxel, paclitaxel, irinotecan, velotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, But are not limited to, rubicin, epirubicin, mitoxantrone, mitomycin, blaromycin, daunorubicin, dactinomycin, pyrabicin, aclarubicin, pepromycin, temsirolimus, temozolomide, But are not limited to, corticosteroids, corticosteroids, cyclophosphamide, cyclophosphamide, melphalan, altretamine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, At least one selected from the group consisting of anagrelide, navelbine, pradrazol, tamoxifen, toremifene, testolactone, anastrozole, letrozole, borozol, bicalutamide, However, But is not limited to.
단계 (c): 상기 약물이 처리된 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 또는 이를 코딩하는 mRNA의 발현 수준을 측정하는 단계에 해당한다.Step (c): Measuring the expression level of the hyaluronic acid synthase of the cancer-mesenchymal stem cell-like cell treated with the drug or the mRNA encoding the same.
본 발명에서는 상기와 같이 시험 물질이 처리된 암-간엽 줄기 유사 세포에서 히알루론산 합성 효소의 발현 수준을 측정할 수 있다. In the present invention, the expression level of hyaluronic acid synthase can be measured in the cancer-mesenchymal stem-like cells treated with the test substance as described above.
본 발명에서 상기 히알루론산 합성 효소(Hyaluronic acid synthase, HAS)는 히알루론산을 합성하는 효소로, 히알루론산 합성 효소 1(Hyaluronic acid synthase 1, HAS1), 히알루론산 합성 효소 2(Hyaluronic acid synthase 2, HAS2) 및 히알루론산 합성 효소 3(Hyaluronic acid synthase 3, HAS3)이 알려져 있으며, 이들 중 히알루론산 합성 효소 2와 히알루론산 합성 효소 3은 섬유아세포와 각질형성세포에서 히알루론산 합성에 중요한 역할을 한다고 알려져 있다. 다만, 본 발명에서 상기와 같이 암-간엽 줄기 유사 세포에서 상기 히알루론산 합성 효소 중에서 특히 히알루론산 합성 효소 2의 발현 수준을 측정하는 것이 암 전이 억제제를 높은 정확도로 스크리닝할 수 있어 바람직하다. In the present invention, the hyaluronic acid synthase (HAS) is an enzyme that synthesizes hyaluronic acid. Hyaluronic acid synthase 1 (HAS1), hyaluronic acid synthase 2 (HAS2) ) And hyaluronic acid synthase 3 (HAS3). Among them,
본 발명에서 상기 히알루론산 합성 효소 1은 서열번호 1로 표시될 수 있고, 상기 히알루론산 합성 효소 2는 서열번호 2로 표시될 수 있으며, 상기 히알루론산 합성 효소 3은 서열번호 3으로 표시될 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the
본 발명에서 상기 히알루론산 합성 효소의 발현 수준을 측정하는 제제는 이에 특이적으로 결합하는 항체일 수 있다.In the present invention, the agent for measuring the expression level of the hyaluronic acid synthase may be an antibody specifically binding thereto.
본 발명에서 상기 "항체"란, 단백질 또는 펩티드 분자의 항원성 부위에 특이적으로 결합할 수 있는 단백질성 분자를 의미하는데, 이러한 항체는, 유전자를 통상적인 방법에 따라 발현벡터에 클로닝하여 상기 마커 유전자에 의해 코딩되는 단백질을 얻고, 얻어진 단백질로부터 통상적인 방법에 의해 제조될 수 있다. 상기 항체의 형태는 특별히 제한되지 않으며 폴리클로날 항체, 모노클로날 항체 또는 항원 결합성을 갖는 것이면 그것의 일부도 본 발명의 항체에 포함되고 모든 면역 글로불린 항체가 포함될 수 있을 뿐만 아니라, 인간화 항체 등의 특수 항체를 포함할 수도 있다. 아울러, 상기 항체는 2개의 전체 길이의 경쇄 및 2개의 전체 길이의 중쇄를 가지는 완전한 형태뿐만 아니라 항체 분자의 기능적인 단편을 포함한다. 항체 분자의 기능적인 단편이란 적어도 항원 결합 기능을 보유하고 있는 단편을 의미하며 Fab, F(ab'), F(ab') 2 및 Fv 등이 될 수 있다.In the present invention, the term "antibody" means a proteinaceous molecule capable of specifically binding to an antigenic site of a protein or peptide molecule. Such an antibody can be produced by cloning a gene into an expression vector according to a conventional method, A protein encoded by the gene can be obtained and can be produced from the obtained protein by a conventional method. The form of the antibody is not particularly limited, and any polyclonal antibody, monoclonal antibody or antigen-binding antibody thereof may be included in the antibody of the present invention and may include all immunoglobulin antibodies, Specific antibodies of the invention. In addition, the antibody comprises a functional fragment of an antibody molecule as well as a complete form having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule means a fragment having at least an antigen-binding function, and can be Fab, F (ab ') 2, F (ab') 2, Fv and the like.
본 발명에 있어서, 상기 항체는 상기 히알루론산 합성 효소에 특이적으로 결합할 수 있는 항체가 될 수 있고, 바람직하게는 상기 각 단백질에 특이적으로 결합할 수 있는 폴리클로날 항체, 모노클로날 항체 또는 그의 일부가 될 수 있다.In the present invention, the antibody may be an antibody capable of specifically binding to the hyaluronic acid synthetase, preferably a polyclonal antibody capable of specifically binding to each protein, a monoclonal antibody Or a part thereof.
또한, 본 발명에서 상기 히알루론산 합성 효소의 발현 수준은 당업계에 공지된 다양한 면역 분석 방법을 통해 실시될 수 있다. 예를 들어, 방사능 면역 분석, 방사능 면역 침전, 면역 침전, ELISA(enzyme-linked immunosorbentassay), 캡처-ELISA, 억제 또는 경재 분석, 그리고 샌드위치 분석을 포함하지만, 이에 한정되는 것은 아니다. In addition, the expression level of the hyaluronic acid synthase in the present invention can be measured by various immunoassay methods known in the art. But are not limited to, radioimmunoassays, radioimmunoprecipitation, immunoprecipitation, enzyme-linked immunosorbent assays (ELISA), capture-ELISA, inhibition or hard tissue analysis, and sandwich assays.
본 발명에서 상기 면역 분석 또는 면역 염색의 방법은 문헌(Enzyme Immunoassay, E. T. Maggio, ed., CRC Press, Boca Raton, Florida, 1980; Gaastra, W., Enzyme-linked immunosorbent assay(ELISA), in Methods in Molecular Biology, Vol. 1, Walker, J.M. ed., Humana Press, NJ, 1984; 및 Ed Harlow and David Lane, Using Antibodies:A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999)에 기재되어 있다. 예를 들어, 본 발명의 방법이 방사능 면역 분석 방법에 따라 실시되는 경우, 방사능 동위원소(예컨대, C14, I125, P32 및 S35)로 표지된 단백질-특이 항체가 이용될 수 있다. Methods of immunoassay or immunostaining in the present invention are described in Enzyme Immunoassay, ET Maggio, ed., CRC Press, Boca Raton, Florida, 1980; Gaastra, W., Enzyme-linked immunosorbent assay (ELISA), in Methods in Humana Press, NJ, 1984, and Ed Harlow and David Lane, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999). For example, if the method of the present invention is carried out according to the method radioactive immunoassay, radioactive isotopes (e. G., C 14, I 125, P 32 and S 35) The protein labeled with - a specific antibody can be used.
또한, 본 발명의 방법이 ELISA 방식으로 실시되는 경우, 본 발명의 특정 실시예는 (i) 시료가 처리된 세포로부터 추출물을 고체 기질의 표면에 코팅하는 단계 (ⅱ) 1차 항체로서의 Ire1 혹은 단백질-특이 항체와 상기 세포 추출물을 반응시키는 단계 (ⅲ) 상기 단계 (ⅱ)의 결과물을 효소가 결합된 2차 항체와 반응시키는 단계 및 (ⅳ) 상기 효소의 활성을 측정하는 단계를 포함할 수 있다. 여기서, 상기 고체 기질로 적합한 것은 탄화수소 폴리머(예컨대, 폴리스틸렌 및 폴리프로필렌), 유리, 금속 또는 젤이며, 가장 바람직하게는 마이크로타이터 플레이트이다. 상기 2차 항체에 결합된 효소는 발색 반응, 형광 반응, 발광 반응 또는 적외선 반응을 촉매하는 효소를 포함하나, 이에 한정되지 않으며, 예를 들어, 알칼린 포스파타아제, β-갈락토시다아제, 호스 래디쉬 퍼옥시다아제, 루시퍼라아제 및 사이토크롬 P450을 포함할 수 있다. 상기한 2차 항체에 결합하는 효소로서 알칼린 포스파타아제가 이용되는 경우에는, 기질로서 브로모클로로인돌일 포스페이트(BCIP), 니트로 블루 테트라졸리움(NBT), 나프톨-ASB1-포스페이트(naphthol-AS-B1-phosphate) 및 ECF(enhanced chemifluorescence)와 같은 발색 반응 기질이 이용되고, 호스 래디쉬 퍼옥시다아제가 이용되는 경우에는 클로로나프톨, 아미노에틸카바졸, 디아미노벤지딘, D-루시페린, 루시게닌(비스-N-메틸아크리디늄 니트레이트), 레소루핀 벤질 에테르, 루미놀, 암플렉스 레드 시약(10-아세틸-3,7-디하이드록시페녹사진), TMB(3,3,5,5-tetramethylbenzidine), ABTS(2,2'-Azine-di[3-ethylbenzthiazoline sulfonate]) 및 o-페닐렌디아민(OPD)과 같은 기질이 이용될 수 있다. 상기 ELISA 방법에서 최종적인 효소의 활성 측정 또는 시그널의 측정은 당업계에 공지된 다양한 방법에 따라 실시될 수 있다. 만일, 레이블로서 바이오틴이 이용된 경우에는 스트렙타비딘으로, 루시퍼라아제가 이용된 경우에는 루시페린으로 시그널을 용이하게 검출할 수 있다. In addition, when the method of the present invention is carried out by an ELISA method, a specific embodiment of the present invention includes the steps of (i) coating an extract from the treated cell with a surface of a solid substrate (ii) (Iii) reacting the result of the step (ii) with an enzyme-bound secondary antibody, and (iv) measuring the activity of the enzyme . Here, suitable as the solid substrate are hydrocarbon polymers (e.g., polystyrene and polypropylene), glass, metal or gel, and most preferably microtiter plates. The enzyme bound to the secondary antibody may include an enzyme catalyzing a chromogenic reaction, a fluorescence reaction, a luminescent reaction, or an infrared reaction, but is not limited thereto. For example, an alkaline phosphatase,? -Galactosidase, Horseradish peroxidase, luciferase, and cytochrome P450. In the case where alkaline phosphatase is used as an enzyme binding to the secondary antibody described above, it is preferable to use, as a substrate, bromochloroindole phosphate (BCIP), nitroblue tetrazolium (NBT), naphthol-AS -Bl-phosphate and ECF (enhanced chemifluorescence) are used. When horseradish peroxidase is used, chloronaphthol, aminoethylcarbazole, diaminobenzidine, D-luciferin, lucigenin (10-acetyl-3,7-dihydroxyphenoxaphone), TMB (3,3,5,5-tetramethylbenzidine), N-methylpyrrolidinone nitrate , ABTS (2,2'-Azine-di [3-ethylbenzthiazoline sulfonate]) and o-phenylenediamine (OPD) can be used. In the ELISA method, the measurement of the final enzyme activity or the measurement of the signal can be performed according to various methods known in the art. If biotin is used as a label, it can be easily detected by streptavidin. When luciferase is used, luciferin can easily detect a signal.
또한, 본 발명에서는 상기와 같이 시험 물질이 처리된 암-간엽 줄기 유사 세포에서 히알루론산 합성 효소를 코딩하는 mRNA의 발현 수준을 측정할 수 있다.In the present invention, the expression level of mRNA encoding hyaluronic acid synthase can be measured in the cancer-mesenchymal stem cell-like cells treated with the test substance as described above.
본 발명에서 상기 히알루론산 합성 효소를 코딩하는 mRNA의 발현 수준을 측정하는 제제는 유전자의 mRNA에 상보적으로 결합하는 센스 및 안티센스 프라이머, 또는 프로브일 수 있다.In the present invention, the agent for measuring the expression level of mRNA encoding the hyaluronic acid synthetase may be a sense and antisense primer complementarily binding to mRNA of a gene, or a probe.
본 발명에서 상기 "프라이머"란, 짧은 자유 3말단 수산화기(free 3' hydroxyl group)를 가지는 핵산 서열로 상보적인 템플레이트(template)와 염기쌍(base pair)을 형성할 수 있고 템플레이트 가닥 복사를 위한 시작 지점으로 기능을 하는 짧은 핵산 서열을 의미한다. 프라이머는 적절한 완충용액 및 온도에서 중합반응(즉, DNA 폴리머레이즈 또는 역전사효소)을 위한 시약 및 상이한 4가지 뉴클레오사이드 트리포스페이트의 존재하에서 DNA 합성이 개시될 수 있다. In the present invention, the term "primer" refers to a nucleotide sequence having a short free 3 'hydroxyl group, capable of forming a base pair with a template complementary to the template, ≪ / RTI > Primers can be used to initiate DNA synthesis in the presence of reagents and four different nucleoside triphosphates for polymerization reactions (i. E., DNA polymerase or reverse transcriptase) at appropriate buffer solutions and temperatures.
본 발명에서 상기 프라이머는 상기 히알루로론산 합성 효소의 mRNA 유전자의 증폭에 사용될 수 있는 프라이머가 될 수 있고, 상기 히알루로니다제의 mRNA 유전자와 상보적으로 결합하여 PCR 방법으로 증폭시킬 수 있는 한, 상기 프라이머의 뉴클레오티드 서열은 제한되지 않는다.In the present invention, the primer may be a primer that can be used for amplification of the mRNA gene of the hyaluronidase, and as long as it can be complementarily bound to the hyaluronidase mRNA gene and amplified by the PCR method, The nucleotide sequence of the primer is not limited.
본 발명에서 상기 "프로브"란, 유전자 또는 mRNA와 특이적 결합을 이룰 수 있는 짧게는 수 염기 내지 길게는 수백 염기에 해당하는 RNA 또는 DNA 등의 핵산 단편을 의미하는데, 올리고뉴클레오티드(oligonucleotide) 프로브, 단쇄 DNA(single stranded DNA) 프로브, 이중쇄 DNA(double stranded DNA) 프로브, RNA 프로브 등의 형태로 제작될 수 있고, 보다 용이하게 검출하기 위하여 라벨링될 수 있다.In the present invention, the term "probe" means a nucleic acid fragment such as RNA or DNA corresponding to a few nucleotides or hundreds of nucleotides that can specifically bind to a gene or an mRNA. Examples of the probe include an oligonucleotide probe, For example, in the form of a single stranded DNA probe, a double stranded DNA probe, an RNA probe, or the like, and may be labeled for easier detection.
본 발명에 있어서, 상기 프로브는 히알루로론산 합성 효소의 mRNA 유전자와 상보적으로 결합할 수 있는 프로브가 될 수 있고, 상기 히알루로니다제의 mRNA 유전자와 상보적으로 결합할 수 있는 한, 상기 프로브의 뉴클레오티드 서열은 제한되지 않는다.In the present invention, the probe may be a probe capable of complementarily binding to an mRNA gene of a hyaluronic acid synthetase, and as long as the probe can complementarily bind to the mRNA gene of hyaluronidase, The nucleotide sequence of SEQ ID NO.
본 발명에서 상기 히알루론산 합성 효소를 코딩하는 mRNA의 발현 수준은중합효소연쇄반응(PCR), 역전사 중합효소연쇄반응(RT-PCR), 실시간 중합효소연쇄반응(Real-time PCR), RNase 보호 분석법(RNase protection assay; RPA), 마이크로어레이(microarray), 및 노던 블롯팅(northern blotting)으로 이루어진 군으로부터 선택되는 1종 이상의 방법을 통해 측정될 수 있다.In the present invention, the expression level of the mRNA encoding the hyaluronic acid synthetase is determined by PCR, reverse transcription polymerase chain reaction (RT-PCR), real-time PCR, RNase protection For example, one or more methods selected from the group consisting of RNase protection assay (RPA), microarray, and northern blotting.
단계 (d): 상기 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 또는 이를 코딩하는 mRNA의 발현 수준이 약물 처리 전에 비하여 감소된 경우, 상기 약물을 암 전이 억제제 후보물질로 판단하는 단계에 해당한다.Step (d): judging the drug as a cancer metastasis inhibitor candidate when the expression level of the hyaluronic acid synthase of the cancer-mesenchymatous stem-like cell or the mRNA encoding the same is decreased as compared with that before the drug treatment.
본 발명에서 상기 단계 (c)에서 측정된 것으로, 약물 처리 후 암-간엽 줄기 유사 세포에서 측정된 히알루론산 합성 효소, 바람직하게는 히알루론산 합성 효소 2의 발현 수준이 약물 처리 전보다 감소한 경우, 상기 약물을 암 치료제 중에서도 특히 암 전이 억제제의 후보물질로 판단할 수 있다. In the present invention, as measured in the step (c), when the expression level of the
단, 상기 단계 (b)에서 약물로 시험 물질과 함께 항암제를 병용 투여한 결과, 약물 처리 후 암-간엽 줄기 유사 세포에서 측정된 히알루론산 합성 효소 2의 발현 수준이 약물 처리 전보다 감소한 경우, 상기 시험 물질 및 항암제 모두를 암 전이 억제제의 후보물질로 판단할 수 있다.However, when the level of expression of
본 발명의 다른 구현 예에 따르면, (1) 암 환자로부터 암-간엽 줄기 유사 세포를 분리하는 단계; (2) 분리된 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2와, 히알루론산 합성 효소 1 및 히알루론산 합성 효소 3 중 적어도 하나 또는 이들을 코딩하는 mRNA의 발현 수준을 측정하는 단계; 및 (3) 상기 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2 또는 이를 코딩하는 mRNA의 발현 수준이 상기 히알루론산 합성 효소 1 및 상기 히알루론산 합성 효소 3 중 적어도 하나의 단백질 또는 이들을 코딩하는 mRNA의 발현 수준보다 높은 경우, 암의 전이 가능성이 높은 것으로 판단하는 단계를 포함하는, 암의 전이 가능성 예측에 대한 정보를 제공하는 방법에 관한 것이다.According to another embodiment of the present invention, there is provided a method of treating cancer, comprising: (1) isolating cancer-stem cell-like cells from a cancer patient; (2) measuring the expression level of
본 발명의 방법을 각각의 단계 별로 상세하게 설명하면 다음과 같다:The method of the present invention will be described in detail in each step as follows:
단계 (1): 암 환자로부터 암-간엽 줄기 유사 세포를 분리하는 단계에 해당한다. Step (1): Is separating cancer-stem cell-like cells from cancer patients.
본 발명에서 상기 암 환자는, 신체 조직의 자율적인 과잉 성장에 의해 비정상적으로 자라난 덩어리인 암(cancer) 혹은 종양(tumor)의 질환이 있는 환자로서, 예를 들면, 뇌암, 폐암, 비소세포성폐암, 결장암, 골암, 췌장암, 피부암, 두부 또는 경부 암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS; central nervous system) 종양, 1차 CNS 림프종, 척수 종양, 및 뇌하수체 선종으로 이루어진 군에서 선택되는 암 질환이 있는 환자일 수 있으나, 바람직하게는 뇌암 환자일 수 있고, 보다 바람직하게는 교모세포종(glioblastoma) 환자일 수 있다. In the present invention, the cancer patient is a patient suffering from a cancer or tumor disease which is abnormally grown by autonomous overgrowth of the body tissue, for example, brain cancer, lung cancer, non-small cell Cancer, ovarian cancer, rectum cancer, gastric cancer, anorectal cancer, colon cancer, breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, pancreatic carcinoma, Cancer of the prostate, chronic or acute leukemia, lymphocytic lymphoma, endometrioid cancer, endometrial carcinoma, thyroid cancer, pituitary cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, Cancer with a cancer selected from the group consisting of bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, and pituitary adenoma Giles number, but may be preferably a brain tumor patient, it may be more preferably glioblastoma patient (glioblastoma).
단, 본 발명에서 상기 환자는 포유류에 해당하는 동물을 모두 포함할 수 있으나, 바람직하게는 인간일 수 있다.However, in the present invention, the patient may include all animals corresponding to mammals, but preferably it may be a human.
또한, 본 발명에서 상기 암-간엽 줄기 유사세포(tumor-associated mesenchymal stem-like cells, tMSLCs)는 제대혈과 골수에 존재하는 골 세포, 연골 세포, 근육 세포 및 섬유 세포 등 골격계 세포로 분화되는 줄기세포인 중간엽 줄기세포와 유사한 특징을 가진 세포를 의미한다. 상기 암-간엽 줄기 유사세포는 중간엽 줄기세포와 유사하게, ⅰ) 플라스틱 부착능을 갖고, ⅱ) 표면 항원 프로파일이 CD105+, CD90+, CD73+, CD45-, CD31- 및 NG2-을 나타내며, ⅲ) 지방 세포, 골 형성 및 연골 형성의 분화능을 보일 수 있다. In addition, in the present invention, the tumor-associated mesenchymal stem-like cells (tMSLCs) are stem cells differentiated into skeletal cells such as bone cells, cartilage cells, muscle cells and fibroblasts existing in cord blood and bone marrow Which is similar to mesenchymal stem cells. CD20 +, CD90 +, CD45-, CD31-, and NG2-, and iii) the adipose tissue of the adipocyte stem cells, wherein the cancer-mesenchymal stem cells are similar to mesenchymal stem cells, Cells, osteogenesis and cartilage formation.
본 발명에서 상기 암-간엽 줄기 유사세포는 암 조직, 바람직하게는 뇌암, 보다 바람직하게는 교모세포종일 수 있다. In the present invention, the cancer-mesenchymal stem cells are cancer tissues, preferably brain cancer, more preferably glioblastoma.
단계 (2): 분리된 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2 또는 이를 코딩하는 mRNA와, 히알루론산 합성 효소 1 및 히알루론산 합성 효소 3 중 적어도 하나의 단백질 또는 이를 코딩하는 mRNA의 발현 수준을 측정하는 단계에 해당한다. Step (2): Expression level of
본 발명에서는 상기 분리된 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2와, 상기 히알루론산 합성 효소 1 및 히알루론산 합성 효소 3 중 적어도 하나의 단백질의 발현 수준을 측정할 수 있다. In the present invention, the expression level of at least one of
본 발명에서 상기 히알루론산 합성 효소의 발현 수준을 측정하는 제제는 이에 특이적으로 결합하는 항체일 수 있다.In the present invention, the agent for measuring the expression level of the hyaluronic acid synthase may be an antibody specifically binding thereto.
본 발명에서 상기 "항체"란, 단백질 또는 펩티드 분자의 항원성 부위에 특이적으로 결합할 수 있는 단백질성 분자를 의미하는데, 이러한 항체는, 유전자를 통상적인 방법에 따라 발현벡터에 클로닝하여 상기 마커 유전자에 의해 코딩되는 단백질을 얻고, 얻어진 단백질로부터 통상적인 방법에 의해 제조될 수 있다. 상기 항체의 형태는 특별히 제한되지 않으며 폴리클로날 항체, 모노클로날 항체 또는 항원 결합성을 갖는 것이면 그것의 일부도 본 발명의 항체에 포함되고 모든 면역 글로불린 항체가 포함될 수 있을 뿐만 아니라, 인간화 항체 등의 특수 항체를 포함할 수도 있다. 아울러, 상기 항체는 2개의 전체 길이의 경쇄 및 2개의 전체 길이의 중쇄를 가지는 완전한 형태뿐만 아니라 항체 분자의 기능적인 단편을 포함한다. 항체 분자의 기능적인 단편이란 적어도 항원 결합 기능을 보유하고 있는 단편을 의미하며 Fab, F(ab'), F(ab') 2 및 Fv 등이 될 수 있다.In the present invention, the term "antibody" means a proteinaceous molecule capable of specifically binding to an antigenic site of a protein or peptide molecule. Such an antibody can be produced by cloning a gene into an expression vector according to a conventional method, A protein encoded by the gene can be obtained and can be produced from the obtained protein by a conventional method. The form of the antibody is not particularly limited, and any polyclonal antibody, monoclonal antibody or antigen-binding antibody thereof may be included in the antibody of the present invention and may include all immunoglobulin antibodies, Specific antibodies of the invention. In addition, the antibody comprises a functional fragment of an antibody molecule as well as a complete form having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule means a fragment having at least an antigen-binding function, and can be Fab, F (ab ') 2, F (ab') 2, Fv and the like.
본 발명에 있어서, 상기 항체는 상기 히알루론산 합성 효소 1 내지 3 각각에 특이적으로 결합할 수 있는 항체가 될 수 있고, 바람직하게는 상기 각 단백질에 특이적으로 결합할 수 있는 폴리클로날 항체, 모노클로날 항체 또는 그의 일부가 될 수 있다.In the present invention, the antibody may be an antibody capable of specifically binding to each of the
본 발명에서 상기 히알루론산 합성 효소 1 내지 3의 발현 수준은 당업계에 공지된 다양한 면역 분석 방법을 통해 실시될 수 있다. 예를 들어, 방사능 면역 분석, 방사능 면역 침전, 면역 침전, ELISA(enzyme-linked immunosorbentassay), 캡처-ELISA, 억제 또는 경재 분석, 그리고 샌드위치 분석을 포함하지만, 이에 한정되는 것은 아니다. In the present invention, the expression levels of the
본 발명에서 상기 면역 분석 또는 면역 염색의 방법은 문헌(Enzyme Immunoassay, E. T. Maggio, ed., CRC Press, Boca Raton, Florida, 1980; Gaastra, W., Enzyme-linked immunosorbent assay(ELISA), in Methods in Molecular Biology, Vol. 1, Walker, J.M. ed., Humana Press, NJ, 1984; 및 Ed Harlow and David Lane, Using Antibodies:A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999)에 기재되어 있다. 예를 들어, 본 발명의 방법이 방사능 면역 분석 방법에 따라 실시되는 경우, 방사능 동위원소(예컨대, C14, I125, P32 및 S35)로 표지된 단백질-특이 항체가 이용될 수 있다. Methods of immunoassay or immunostaining in the present invention are described in Enzyme Immunoassay, ET Maggio, ed., CRC Press, Boca Raton, Florida, 1980; Gaastra, W., Enzyme-linked immunosorbent assay (ELISA), in Methods in Humana Press, NJ, 1984, and Ed Harlow and David Lane, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999). For example, if the method of the present invention is carried out according to the method radioactive immunoassay, radioactive isotopes (e. G., C 14, I 125, P 32 and S 35) The protein labeled with - a specific antibody can be used.
또한, 본 발명의 방법이 ELISA 방식으로 실시되는 경우, 본 발명의 특정 실시예는 (i) 시료가 처리된 세포로부터 추출물을 고체 기질의 표면에 코팅하는 단계; (ⅱ) 1차 항체로서의 Ire1 혹은 단백질-특이 항체와 상기 세포 추출물을 반응시키는 단계; (ⅲ) 상기 단계 (ⅱ)의 결과물을 효소가 결합된 2차 항체와 반응시키는 단계; 및 (ⅳ) 상기 효소의 활성을 측정하는 단계를 포함할 수 있다. 여기서, 상기 고체 기질로 적합한 것은 탄화수소 폴리머(예컨대, 폴리스틸렌 및 폴리프로필렌), 유리, 금속 또는 젤이며, 가장 바람직하게는 마이크로타이터 플레이트이다. 상기 2차 항체에 결합된 효소는 발색 반응, 형광 반응, 발광 반응 또는 적외선 반응을 촉매하는 효소를 포함하나, 이에 한정되지 않으며, 예를 들어, 알칼린 포스파타아제, β-갈락토시다아제, 호스 래디쉬 퍼옥시다아제, 루시퍼라아제 및 사이토크롬 P450을 포함할 수 있다. 상기한 2차 항체에 결합하는 효소로서 알칼린 포스파타아제가 이용되는 경우에는, 기질로서 브로모클로로인돌일 포스페이트(BCIP), 니트로 블루 테트라졸리움(NBT), 나프톨-ASB1-포스페이트(naphthol-AS-B1-phosphate) 및 ECF(enhanced chemifluorescence)와 같은 발색 반응 기질이 이용되고, 호스 래디쉬 퍼옥시다아제가 이용되는 경우에는 클로로나프톨, 아미노에틸카바졸, 디아미노벤지딘, D-루시페린, 루시게닌(비스-N-메틸아크리디늄 니트레이트), 레소루핀 벤질 에테르, 루미놀, 암플렉스 레드 시약(10-아세틸-3,7-디하이드록시페녹사진), TMB(3,3,5,5-tetramethylbenzidine), ABTS(2,2'-Azine-di[3-ethylbenzthiazoline sulfonate]) 및 o-페닐렌디아민(OPD)과 같은 기질이 이용될 수 있다. 상기 ELISA 방법에서 최종적인 효소의 활성 측정 또는 시그널의 측정은 당업계에 공지된 다양한 방법에 따라 실시될 수 있다. 만일, 레이블로서 바이오틴이 이용된 경우에는 스트렙타비딘으로, 루시퍼라아제가 이용된 경우에는 루시페린으로 시그널을 용이하게 검출할 수 있다. In addition, when the method of the present invention is carried out by an ELISA method, a specific embodiment of the present invention comprises the steps of (i) coating the surface of a solid substrate with an extract from a sample-treated cell; (Ii) reacting said cell extract with Ire1 or a protein-specific antibody as a primary antibody; (Iii) reacting the result of step (ii) with an enzyme-conjugated secondary antibody; And (iv) measuring the activity of the enzyme. Here, suitable as the solid substrate are hydrocarbon polymers (e.g., polystyrene and polypropylene), glass, metal or gel, and most preferably microtiter plates. The enzyme bound to the secondary antibody may include an enzyme catalyzing a chromogenic reaction, a fluorescence reaction, a luminescent reaction, or an infrared reaction, but is not limited thereto. For example, an alkaline phosphatase,? -Galactosidase, Horseradish peroxidase, luciferase, and cytochrome P450. In the case where alkaline phosphatase is used as an enzyme binding to the secondary antibody described above, it is preferable to use, as a substrate, bromochloroindole phosphate (BCIP), nitroblue tetrazolium (NBT), naphthol-AS -Bl-phosphate and ECF (enhanced chemifluorescence) are used. When horseradish peroxidase is used, chloronaphthol, aminoethylcarbazole, diaminobenzidine, D-luciferin, lucigenin (10-acetyl-3,7-dihydroxyphenoxaphone), TMB (3,3,5,5-tetramethylbenzidine), N-methylpyrrolidinone nitrate , ABTS (2,2'-Azine-di [3-ethylbenzthiazoline sulfonate]) and o-phenylenediamine (OPD) can be used. In the ELISA method, the measurement of the final enzyme activity or the measurement of the signal can be performed according to various methods known in the art. If biotin is used as a label, it can be easily detected by streptavidin. When luciferase is used, luciferin can easily detect a signal.
또한, 본 발명에서는 상기 분리된 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2의 mRNA와, 상기 히알루론산 합성 효소 1 및 히알루론산 합성 효소 3 중 적어도 하나의 단백질을 코딩하는 mRNA의 발현 수준을 측정할 수 있다.In the present invention, the expression level of mRNA encoding
본 발명에서 상기 히알루론산 합성 효소 1 내지 3를 코딩하는 mRNA의 발현 수준을 측정하는 제제는 유전자의 mRNA에 상보적으로 결합하는 센스 및 안티센스 프라이머, 또는 프로브일 수 있다.In the present invention, the agent for measuring the expression level of the mRNA encoding the
본 발명에서 상기 "프라이머"란, 짧은 자유 3말단 수산화기(free 3' hydroxyl group)를 가지는 핵산 서열로 상보적인 템플레이트(template)와 염기쌍(base pair)을 형성할 수 있고 템플레이트 가닥 복사를 위한 시작 지점으로 기능을 하는 짧은 핵산 서열을 의미한다. 프라이머는 적절한 완충용액 및 온도에서 중합반응(즉, DNA 폴리머레이즈 또는 역전사효소)을 위한 시약 및 상이한 4가지 뉴클레오사이드 트리포스페이트의 존재하에서 DNA 합성이 개시될 수 있다. In the present invention, the term "primer" refers to a nucleotide sequence having a short free 3 'hydroxyl group, capable of forming a base pair with a template complementary to the template, ≪ / RTI > Primers can be used to initiate DNA synthesis in the presence of reagents and four different nucleoside triphosphates for polymerization reactions (i. E., DNA polymerase or reverse transcriptase) at appropriate buffer solutions and temperatures.
본 발명에서 상기 프라이머는 상기 히알루로론산 합성 효소 1 내지 3 각각의 mRNA 유전자의 증폭에 사용될 수 있는 프라이머가 될 수 있고, 상기 히알루로니다제의 mRNA 유전자와 상보적으로 결합하여 PCR 방법으로 증폭시킬 수 있는 한, 상기 프라이머의 뉴클레오티드 서열은 제한되지 않는다.In the present invention, the primer may be a primer that can be used for amplification of the mRNA gene of each of the
본 발명에서 상기 "프로브"란, 유전자 또는 mRNA와 특이적 결합을 이룰 수 있는 짧게는 수 염기 내지 길게는 수백 염기에 해당하는 RNA 또는 DNA 등의 핵산 단편을 의미하는데, 올리고뉴클레오티드(oligonucleotide) 프로브, 단쇄 DNA(single stranded DNA) 프로브, 이중쇄 DNA(double stranded DNA) 프로브, RNA 프로브 등의 형태로 제작될 수 있고, 보다 용이하게 검출하기 위하여 라벨링될 수 있다.In the present invention, the term "probe" means a nucleic acid fragment such as RNA or DNA corresponding to a few nucleotides or hundreds of nucleotides that can specifically bind to a gene or an mRNA. Examples of the probe include an oligonucleotide probe, For example, in the form of a single stranded DNA probe, a double stranded DNA probe, an RNA probe, or the like, and may be labeled for easier detection.
본 발명에 있어서, 상기 프로브는 히알루로론산 합성 효소 1 내지 3 각각의 mRNA 유전자와 상보적으로 결합할 수 있는 프로브가 될 수 있고, 상기 히알루로니다제의 mRNA 유전자와 상보적으로 결합할 수 있는 한, 상기 프로브의 뉴클레오티드 서열은 제한되지 않는다.In the present invention, the probe may be a probe capable of complementarily binding to mRNA genes of
본 발명에서 상기 히알루론산 합성 효소 1 내지 3를 코딩하는 mRNA의 발현 수준은 중합효소연쇄반응(PCR), 역전사 중합효소연쇄반응(RT-PCR), 실시간 중합효소연쇄반응(Real-time PCR), RNase 보호 분석법(RNase protection assay; RPA), 마이크로어레이(microarray), 및 노던 블롯팅(northern blotting)으로 이루어진 군으로부터 선택되는 1종 이상의 방법을 통해 측정될 수 있다.In the present invention, the expression level of the mRNA encoding the
단계 (3): 상기 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2 또는 이를 코딩하는 mRNA의 발현 수준이 상기 히알루론산 합성 효소 1 및 상기 히알루론산 합성 효소 3 중 적어도 하나의 단백질 또는 이를 코딩하는 mRNA의 발현 수준보다 높은 경우, 암의 전이 가능성이 높은 것으로 판단하는 단계에 해당한다.Wherein the expression level of the
본 발명에서 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2의 발현 수준이 동일한 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 1 및 히알루론산 합성 효소 3 중 적어도 하나의 단백질의 발현 수준보다 높은 경우, 암의 침윤성 및 전이성이 높은 것으로 판단할 수 있으며, 또한 암 환자의 예후가 나쁠 것으로 예측할 수 있다. 보다 바람직하게는 상기 히알루론산 합성 효소 2의 발현 수준이 히알루론산 합성 효소 1 및 히알루론산 합성 효소 3 각각의 발현 수준 보다 높은 경우, 암의 침윤성 및 전이성이 높은 것으로 판단할 수 있다. In the present invention, when the expression level of
또한, 본 발명에서 상기 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2를 코딩하는 mRNA의 발현 수준이 동일한 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 1 및 히알루론산 합성 효소 3 중 적어도 하나의 단백질을 코딩하는 mRNA의 발현 수준보다 높은 경우, 암의 침윤성 및 전이성이 높은 것으로 판단할 수 있으며, 암 환자의 예후가 나쁠 것으로 예측할 수 있다. 보다 바람직하게는 상기 히알루론산 합성 효소 2를 코딩하는 mRNA의 발현 수준이 히알루론산 합성 효소 1를 코딩하는 mRNA 및 히알루론산 합성 효소 3을 코딩하는 mRNA 각각의 발현 수준 보다 높은 경우, 암의 침윤성 및 전이성이 높은 것으로 판단할 수 있다.In addition, in the present invention, at least one of
본 발명은 암 환자로부터 분리된 암-간엽 줄기 유사 세포에 있어서 히알루론산 합성 효소 2의 발현 수준을 측정함으로써 암 전이 억제제를 높은 정확도로 스크리닝할 수 있다. The present invention can screen cancer metastasis inhibitor with high accuracy by measuring the expression level of
또한, 본 발명은 암 환자로부터 분리된 암-간엽 줄기 유사 세포에서 히알루론산 합성 효소 2와, 히알루론산 합성 효소 1 또는 3의 발현 수준을 비교함으로써 암의 전이 가능성을 높은 정확도로 예측할 수 있다. Further, the present invention can predict the cancer metastasis possibility with high accuracy by comparing the expression levels of
도 1은 본 발명의 일 실시예에서, 트렌스 웰에 tMSLCs와 GBM 세포를 공동 배양한 후 GBM 세포의 이동에 관한 개략도를 나타낸 것이다.
도 2의 (a)는 본 발명의 일 실시예에서, 트렌스 웰에 tMSLCs와 GBM 세포를 공동 배양한 후 GBM 세포의 사진을 나타낸 것이다.
도 2의 (b)는 본 발명의 일 실시예에서, 트렌스 웰에 tMSLCs와 GBM 세포를 공동 배양한 후 이동한 GBM 세포의 수를 그래프로 나타낸 것이다. ***은 대조군 대비 p < 0.001인 것을 의미한다.
도 3은 본 발명의 일 실시예에서, tMSLCs에 의해 전조정된 콜라겐-기반 ECM에서 GBM 세포의 침윤성을 분석하기 위한 실험적 계획의 개략도를 나타낸 것이다.
도 4의 (a)는 본 발명의 일 실시예에서, tMSLCs에 의해 전조정된 콜라겐-기반 ECM으로 침윤한 X01 GBM 세포의 H&E 염색 사진을 나타낸 것이다.
도 4의 (b)는 본 발명의 일 실시예에서, tMSLCs에 의해 전조정된 콜라겐-기반 ECM으로 침윤한 X01 GBM 세포의 수를 그래프로 나타낸 것이다. *은 대조군 대비 p < 0.05인 것을 의미한다.
도 5는 본 발명의 일 실시예에서 X01 GBM 세포 및 tMSLCs에서 ECM 성분 및 리모델링 효소의 반정량적 RT-PCR 결과를 나타낸 것이다.
도 6의 (a)는 본 발명의 일 실시예에서 VCAN 또는 HAS2에 대한 siRNA로 형질 전환된 X01 GBM 단독 세포 혹은 tMSLCs와 공동 배양 후 X01 GBM 세포의 상처 치료 분석 결과 후 사진을 나타낸 것이다.
도 6의 (b)는 본 발명의 일 실시예에서 X01 GBM 단독 세포 혹은 tMSLCs와 공동 배양된 X01 GBM 세포를 VCAN 또는 HAS2에 대한 siRNA로 형질 전환시킨 경우 상처 치유율의 변화를 그래프로 나타낸 것이다.
도 7의 (a)는 본 발명의 일 실시예에서 VCAN 또는 HAS2에 대한 siRNA로 형질 전환된 X01 GBM 단독 세포 혹은 tMSLCs와 공동 배양 후 X01 GBM 세포의 이동 사진을 나타낸 것이다.
도 7의 (b)는 본 발명의 일 실시예에서 X01 GBM 단독 세포 혹은 tMSLCs와 공동 배양된 X01 GBM 세포를 VCAN 또는 HAS2에 대한 siRNA로 형질 전환시킨 경우 이동한 XO1 GBM 세포수를 그래프로 나타낸 것이다.
도 8의 (a)는 본 발명의 일 실시예에서, 트렌스 웰에서 X01 GBM 세포에 히알루론산을 처리한 결과 X01 GBM 세포의 이동 사진을 나타낸 것이다.
도 8의 (b)는 본 발명의 일 실시예에서, 트렌스 웰에서 X01 GBM 세포에 히알루론산을 처리한 결과 이동한 XO1 GBM 세포수를 그래프로 나타낸 것이다.
도 9는 XO1 GBM 세포, tMSLCs0903 또는 이들의 공동 배양 시 HAS2의 발현 수준을 웨스턴 블럿 및 반정량적 RT-PCR로 분석한 결과를 나타낸 것이다. 단, 상기 도 9에서 'X01tMSLCs0903'은 tMSLCs0903와 공동 배양된 X01 GBM 세포를 나타낸 것이고, 'tMSLCs0903X01'은 X01 GBM 세포와 공동 배양된 tMSLCs0903를 나타낸 것이다.
도 10은 본 발명의 일 실시예에서 XO1 GBM 세포, tMSLCs0903 또는 이들의 공동 배양 시 히알루론산(HA)의 발현 수준을 ELISA로 분석한 결과를 그래프로 나타낸 것이다. ***은 대조군 대비 p < 0.001인 것을 의미한다.
도 11은 본 발명의 일 실시예에서 siRNA로 처리한 tMSLCs0903에서 히알루론산(HA)의 발현 수준을 ELISA로 분석한 결과를 그래프로 나타낸 것이다. ***은 대조군 대비 p < 0.001인 것을 의미한다.
도 12는 본 발명의 일 실시예에서 XO1 GBM 세포 및 tMSLCs0903의 사이토카인 분석 결과를 나타낸 것이다.
도 13은 본 발명의 일 실시예에서 각 siRNA로 처리한 tMSLCs0903에서 HAS2의 웨스턴 블럿 분석 결과를 나타낸 것이다.
도 14는 본 발명의 일 실시예에서 각 siRNA로 처리한 tMSLCs0903에서 히알루론산(HA)의 발현 수준을 ELISA로 분석한 결과를 그래프로 나타낸 것이다. ***은 대조군 대비 p < 0.001인 것을 의미한다.
도 15는 본 발명의 일 실시예에서 C5a 항체로 처리한 tMSLCs0903에서 히알루론산 합성 효소 2(HAS2)의 발현 수준을 웨스턴 블럿으로 분석한 결과를 나타낸 것이다.
도 16은 본 발명의 일 실시예에서 C5a 항체로 처리한 tMSLCs0903에서 히알루론산 합성 효소 2(HAS2)의 발현 수준을 ELISA로 분석한 결과를 그래프로 나타낸 것이다. ***은 대조군 대비 p < 0.001인 것을 의미한다.
도 17은 본 발명의 일 실시예에서 C5aR1에 대한 siRNA로 처리한 tMSLCs0903에서 히알루론산 합성 효소 2(HAS2)의 발현 수준을 웨스턴 블럿으로 분석한 결과를 나타낸 것이다.
도 18은 본 발명의 일 실시예에서 C5aR1에 대한 siRNA로 처리한 tMSLCs0903에서 히알루론산 합성 효소 2(HAS2)의 발현 수준을 ELISA로 분석한 결과를 그래프로 나타낸 것이다. **은 대조군 대비 p < 0.01인 것을 의미한다.
도 19는 본 발명의 일 실시예에서 rh-C5a로 처리한 X01 GBM 세포에서 히알루론산 합성 효소 2(HAS2)의 발현 수준을 웨스턴 블럿으로 분석한 결과를 나타낸 것이다. 단, 상기 도 19에서 tMSLCs0903에서 히알루론산 합성 효소 2(HAS2)는 양성 대조군으로 나타낸 것이고, 'S.E'는 단기 노출(short exposed), 'L.E'는 장기 노출(long exposed)을 의미한다.
도 20은 본 발명의 일 실시예에서 X01 GBM 세포(X01), tMSLCs0903, 및 이들의 공동 배양 조건에서 C5aR1의 발현 수준을 웨스턴 블럿으로 분석한 결과를 나타낸 것이다. 단, 상기 도 20에서 'X01tMSLCs0903'은 tMSLCs0903와 공동 배양된 X01 GBM 세포를 나타낸 것이고, 'tMSLCs0903X01'은 X01 GBM 세포와 공동 배양된 tMSLCs0903를 나타낸 것이다.
도 21은 본 발명의 일 실시예에서, C5a 중화 항체의 존재 하에서 X01 GBM 세포, 및 tMSLCs0903와 공동 배양된 X01 GBM 세포에서 이동 능력을 분석한 결과를 나타낸 것이다.
도 22는 본 발명의 일 실시예에서, C5a 중화 항체를 처리한 후 이동한 X01 GBM 세포 및 tMSLCs0903와 공동 배양된 X01 GBM 세포의 수를 그래프로 나타낸 것이다. ***은 대조군 대비 p < 0.001인 것을 의미한다.
도 23은 본 발명의 일 실시예에서 C5에 대한 siRNA로 처리한 tMSLCs0903에서 ERK, MAPK, AKT, JAK1 및 STAT3의 활성화 상태를 웨스턴 블럿으로 분석한 결과를 나타낸 것이다.
도 24는 본 발명의 일 실시예에서, tMSLCs0903에 MEK 억제제(U0126), PI3K/AKT 억제제(LY294002), JAK1 억제제(P6) 또는 STAT3 억제제(WP1066)를 처리한 후 히알루론산 합성 효소 2(HAS2)의 발현 수준을 qRT-PCR로 분석한 결과를 그래프로 나타낸 것이다. ***은 대조군 대비 p < 0.001인 것을 의미한다.
도 25는 본 발명의 일 실시예에서, tMSLCs0903에 MEK 억제제(U0126), PI3K/AKT 억제제(LY294002), JAK1 억제제(P6) 또는 STAT3 억제제(WP1066)를 처리한 후 히알루론산(HA)의 발현 수준을 ELISA로 분석한 결과를 그래프로 나타낸 것이다. ***은 대조군 대비 p < 0.001인 것을 의미한다.
도 26은 본 발명의 일 실시예에서, tMSLCs0903에 MEK 억제제(U0126)를 처리한 후 히알루론산 합성 효소 2(HAS2)의 발현 수준을 웨스턴 블럿으로 분석한 결과를 그래프로 나타낸 것이다.
도 27은 본 발명의 일 실시예에서, tMSLCs0903에 MEK 억제제(U0126)를 처리한 후 히알루론산(HA)의 발현 수준을 ELISA로 분석한 결과를 그래프로 나타낸 것이다. ***은 대조군 대비 p < 0.001인 것을 의미한다.
도 28은 본 발명의 일 실시예에서 C5a 항체를 처리한 후 ERK MAPK의 활성화 상태를 웨스턴 블럿으로 분석한 결과를 나타낸 것이다.
도 29의 (a)는 본 발명의 일 실시예에서 ERK MAPK에 대한 siRNA 처리한 후 X01 GBM 세포(X01 alone), 및 tMSLCs0903와 공동 배양된 X01 GBM 세포(tMSLCs0903)에서 이동 능력을 분석한 결과를 나타낸 것이다. FIG. 1 is a schematic diagram of migration of GBM cells after co-culturing tMSLCs and GBM cells in a transwell in an embodiment of the present invention.
Figure 2 (a) is a photograph of GBM cells after co-culturing tMSLCs and GBM cells in a transwell in an embodiment of the present invention.
FIG. 2 (b) is a graph showing the number of migrated GBM cells after co-culturing tMSLCs and GBM cells in a transwell in an embodiment of the present invention. *** means p < 0.001 as compared to the control group.
Figure 3 shows a schematic diagram of an experimental design for analyzing the invasiveness of GBM cells in a collagen-based ECM pre-conditioned by tMSLCs, in one embodiment of the invention.
Figure 4 (a) shows H & E staining of X01 GBM cells infiltrated with collagen-based ECM pre-conditioned by tMSLCs in one embodiment of the invention.
Figure 4 (b) is a graphical representation of the number of X01 GBM cells infiltrated with collagen-based ECM preconditioned by tMSLCs, in one embodiment of the invention. * Means p < 0.05 compared to the control.
Figure 5 shows semi-quantitative RT-PCR results of ECM components and remodeling enzymes in X01 GBM cells and tMSLCs in one embodiment of the invention.
FIG. 6 (a) is a photograph of X01 GBM cells co-cultured with X01 GBM monoclonal or tMSLCs transformed with siRNA for VCAN or HAS2 according to an embodiment of the present invention,
FIG. 6 (b) is a graph showing changes in wound healing rate when X01 GBM single cells or X01 GBM cells co-cultured with tMSLCs were transformed with siRNA for VCAN or HAS2 in one embodiment of the present invention.
FIG. 7 (a) is a photograph showing the movement of X01 GBM cells after co-culture with X01 GBM single cells or tMSLCs transformed with siRNA for VCAN or HAS2 in one embodiment of the present invention.
FIG. 7 (b) is a graph showing the number of migrated XO1 GBM cells when X01 GBM single cells or X01 GBM cells co-cultured with tMSLCs were transformed with siRNA for VCAN or HAS2 in one embodiment of the present invention .
8 (a) shows a photograph of X01 GBM cells as a result of treatment of hyaluronic acid in X01 GBM cells in Transwell in an embodiment of the present invention.
FIG. 8 (b) is a graph showing the number of XO1 GBM cells migrated as a result of treating hyaluronic acid in X01 GBM cells in a transwell in an embodiment of the present invention.
FIG. 9 shows the results of Western blot and semi-quantitative RT-PCR analysis of expression levels of HAS2 in XO1 GBM cells, tMSLCs0903, or their co-cultures. In FIG. 9, 'X01 tMSLCs0903 ' represents X01 GBM cells co-cultured with tMSLCs0903, and 'tMSLCs0903 X01 ' represents tMSLCs0903 co-cultured with X01 GBM cells.
FIG. 10 is a graph showing the results of ELISA analysis of the expression levels of hyaluronic acid (HA) in XO1 GBM cells, tMSLCs0903, or their co-cultures in an embodiment of the present invention. *** means p < 0.001 as compared to the control group.
FIG. 11 is a graph showing the results of ELISA analysis of the expression level of hyaluronic acid (HA) in tMSLCs0903 treated with siRNA in one embodiment of the present invention. *** means p < 0.001 as compared to the control group.
Figure 12 shows cytokine analysis results of XO1 GBM cells and tMSLCs0903 in one embodiment of the present invention.
Figure 13 shows Western blot analysis of HAS2 in tMSLCs0903 treated with each siRNA in one embodiment of the invention.
FIG. 14 is a graph showing the results of ELISA analysis of the expression level of hyaluronic acid (HA) in tMSLCs0903 treated with each siRNA in one embodiment of the present invention. *** means p < 0.001 as compared to the control group.
FIG. 15 shows Western blot analysis of the expression level of hyaluronic acid synthase 2 (HAS2) in tMSLCs0903 treated with C5a antibody in one embodiment of the present invention.
16 is a graph showing the results of ELISA analysis of the expression level of hyaluronic acid synthase 2 (HAS2) in tMSLCs0903 treated with a C5a antibody in one embodiment of the present invention. *** means p < 0.001 as compared to the control group.
17 shows the Western blot analysis of the expression level of hyaluronic acid synthase 2 (HAS2) in tMSLCs0903 treated with siRNA against C5aR1 in one embodiment of the present invention.
18 is a graph showing the results of ELISA analysis of the expression level of hyaluronic acid synthase 2 (HAS2) in tMSLCs0903 treated with siRNA against C5aR1 in one embodiment of the present invention. ** means p < 0.01 compared to the control group.
FIG. 19 shows Western blot analysis of the expression level of hyaluronic acid synthase 2 (HAS2) in X01 GBM cells treated with rh-C5a in one embodiment of the present invention. 19, hyaluronic acid synthetase 2 (HAS2) is expressed as a positive control in tMSLCs0903, 'S.E' is short exposure, and 'L.E' is long exposure do.
Figure 20 shows Western blot analysis of expression levels of C5aR1 in X01 GBM cells (X01), tMSLCs0903, and their co-culture conditions in one embodiment of the present invention. In FIG. 20, 'X01 tMSLCs0903 ' represents X01 GBM cells co-cultured with tMSLCs0903, and 'tMSLCs0903 X01 ' represents tMSLCs0903 co-cultured with X01 GBM cells.
Figure 21 shows the results of analysis of migration ability in X01 GBM cells in the presence of C5a neutralizing antibody and X01 GBM cells co-cultured with tMSLCs0903 in one embodiment of the present invention.
Figure 22 is a graphical representation of the number of X01 GBM cells transferred after treatment with C5a neutralizing antibody and X01 GBM cells co-cultured with tMSLCs0903 in one embodiment of the present invention. *** means p < 0.001 as compared to the control group.
23 shows Western blot analysis of activation states of ERK, MAPK, AKT, JAK1 and STAT3 in tMSLCs0903 treated with siRNA against C5 in one embodiment of the present invention.
Figure 24 shows that in one embodiment of the present invention hyaluronic acid synthase 2 (HAS2) is treated after treatment of MMS inhibitor (U0126), PI3K / AKT inhibitor (LY294002), JAK1 inhibitor (P6) or STAT3 inhibitor (WP1066) The results of the analysis of the expression level by qRT-PCR are shown in the graph. *** means p < 0.001 as compared to the control group.
Figure 25 shows that in one embodiment of the invention the expression level of hyaluronic acid (HA) after treatment of MMS inhibitor (U0126), PI3K / AKT inhibitor (LY294002), JAK1 inhibitor (P6) or STAT3 inhibitor (WP1066) Was analyzed by ELISA. *** means p < 0.001 as compared to the control group.
FIG. 26 is a graph showing the Western blot analysis of the expression level of hyaluronic acid synthase 2 (HAS2) after treatment of MMS inhibitor (U0126) with tMSLCs0903 in one embodiment of the present invention.
Figure 27 is a graph showing the results of ELISA analysis of the expression level of hyaluronic acid (HA) after treatment of MMS inhibitor (U0126) with tMSLCs0903 in one embodiment of the present invention. *** means p < 0.001 as compared to the control group.
FIG. 28 shows Western blot analysis of the activation state of ERK MAPK after treatment with C5a antibody in one embodiment of the present invention.
29 (a) shows the results of analysis of migration ability in X01 GBM cells (X01 alone) and X01 GBM cells (tMSLCs0903) co-cultured with tMSLCs0903 after treatment with siRNA for ERK MAPK in one embodiment of the present invention .
이하, 본 발명을 하기의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.
실시예Example
화학 약제 및 항체Chemicals and Antibodies
p-ERK1/2, ERK1/2, p-T308-AKT, AKT, p-Y705-STAT3, JAK1에 대한 항체는 Cell Signaling Technology (Beverly, MA, USA)에서 구입하였고, STAT3 및 p-T1022-JAK1에 대한 항체는 Santa Cruz Biotechnology (Santa Cruz, CA, USA)에서 구입하였으며, HAS2 및 C5R1에 대한 항체는 Abcam (Cambridge, UK)에서 구입하였다. 4,6-디아미디노-2-페닐인돌 (4,6-diamidino-2-phenylindole, DAPI)은 Sigma (St Louis, MO, USA)에서 구입하였고, rh-C5a 단백질과 CD105 및 C5a에 대한 항체는 R&D Systems (Minneapolis, MN, USA)에서 구입하였다. MEK (U0126), PI3K (LY294002), JAK1 (P6) 및 STAT3 (WP1066) 특이적 화학적 억제제는 Calbiochem (San Diego, CA, USA)에서 구입하였다. 항-염소 Alexa Fluor 488, 항-마우스 Alexa Fluor 546는 Invitrogen (Carlsbad, CA, USA)에서 구입하였다. 항-마우스 IgG-HRP, 항-염소 IgG-HRP 및 항-토끼 Ig-HRP는 Santa Cruz biotechnology (Santa Cruz, CA, USA)에서 구입하였다. 히알루론산 (Low molecular weight; 15-40 kDa)은 R&D systems (Minneapolis, MN, USA)에서 구입하였다. Antibodies to p-ERK1 / 2, ERK1 / 2, p-T308-AKT, AKT and p-Y705-STAT3 and JAK1 were purchased from Cell Signaling Technology (Beverly, MA, USA) and STAT3 and p-T1022-JAK1 Were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Antibodies against HAS2 and C5R1 were purchased from Abcam (Cambridge, UK). 4,6-diamidino-2-phenylindole (DAPI) was purchased from Sigma (St Louis, MO, USA) and the antibody against rh-C5a protein and CD105 and C5a Were purchased from R & D Systems (Minneapolis, MN, USA). MEK (U0126), PI3K (LY294002), JAK1 (P6) and STAT3 (WP1066) specific chemical inhibitors were purchased from Calbiochem (San Diego, CA, USA). Anti-goat Alexa Fluor 488 and anti-mouse Alexa Fluor 546 were purchased from Invitrogen (Carlsbad, CA, USA). Anti-mouse IgG-HRP, anti-goat IgG-HRP and anti-rabbit Ig-HRP were purchased from Santa Cruz biotechnology (Santa Cruz, CA, USA). Hyaluronic acid (Low molecular weight; 15-40 kDa) was purchased from R & D systems (Minneapolis, MN, USA).
암-cancer- 간엽Liver 줄기 유사 세포( Stem-like cells ( tMSLCtMSLC ) 및 교모세포종() And glioblastoma ( GBMCPD ) 세포의 공동 배양) Co-culture of cells
포어 사이즈가 0.4㎛인 트랜스웰(transwell)을 준비한 뒤, tMSLC0903 (2.5 X 105)를 트랜스웰의 상부 챔버에 접종하고, X01 GBM cells (1.5 X 105)를 하부 챔버에 접종하여 공동 배양 후 3일 동안 세포 이동을 분석하였다. After transwell with a pore size of 0.4 탆 was prepared, tMSLC0903 (2.5 × 10 5 ) was inoculated into the upper chamber of the transwell and X01 GBM cells (1.5 × 10 5 ) were inoculated into the lower chamber and co-cultured Cell migration was analyzed for 3 days.
GBMCPD 세포 및 Cells and tMSLCs의of tMSLCs 배양 culture
68세 여성인 교모세포종 환자로부터 GBM 세포를 분리하여 준비하고(X01 GBM 세포), 1% 페니실린 및 스트렙토 마이신을 포함하며, 10% 열-불활성화된 소 태아 혈청 (Lonza, Basel, Switzerland)이 보충된 둘베코 변형 이글 배지 (Gibco, Korea, Seoul)에 배양하였다. GBM cells were isolated from a 68 year-old female glioblastoma patient (X01 GBM cells), supplemented with 10% heat-inactivated fetal bovine serum (Lonza, Basel, Switzerland) containing 1% penicillin and streptomycin (Dulbecco's modified Eagle's medium (Gibco, Korea, Seoul).
상기 동일한 환자로부터 t-MSLCs를 분리한 뒤(tMSLC09-03) 비부착 세포만을 인산 완충 식염수(phosphate-buffered saline, PBS)로 세척하고, 오직 부착 tMSLCs만을 수집하여 10% FBS (Lonza), 2 mM L-글루타민 (Mediatech), 및 항생-항진균성 용액 (Gibco, Seoul, Korea)을 포함하는 MEMα (Mediatech)에서 배양하였다. After isolating t-MSLCs from the same patient (tMSLC09-03), only unattached cells were washed with phosphate-buffered saline (PBS) and only attached tMSLCs were collected and resuspended in 10% FBS (Lonza), 2 mM (Mediatech) containing L-glutamine (Mediatech), and antibiotic-antifungal solution (Gibco, Seoul, Korea).
세포 cell 이동능의Mobile 분석 analysis
GBM 세포의 이동성을 분석하기 위하여, 포어 사이즈가 8㎛인 트랜스웰(Corning Glass, Seoul, Korea)을 이용하였다. 우선, GBM 세포 (2 X 104)를 상기 트랜스웰의 상부 웰에 로딩하고, 24시간 동안 배양하였다. 필터의 하부 표면으로 이동한 세포를 고정한 뒤 Diff Quick kit (Fisher, Pittsburgh, PA, USA)로 염색하였다. 이동한 세포의 수를 웰 당 세개의 현미경 필드(microscopic fileds)로 계수하였다. To analyze the mobility of GBM cells, Transwell (Corning Glass, Seoul, Korea) having a pore size of 8 mu m was used. First, GBM cells (2 X 10 4 ) were loaded into the upper well of the transwell and cultured for 24 hours. Cells migrated to the lower surface of the filter were fixed and stained with the Diff Quick kit (Fisher, Pittsburgh, PA, USA). The number of migrated cells was counted in three microscopic fields per well.
tMSLCstMSLCs 유래 origin 세포외Extracellular 기질에서 From the substrate GBMCPD 세포의 기관형 침윤성 Tumor invasion of cells
tMSLC0903을 콜라겐 매트릭스에 접종한 후 3일 동안 배양하여 tMSLC0903-유래 ECM 리모델링을 하였다. 그 후, 퓨로마이신(puromycin)을 이용하여 tMSLC0903 세포를 사멸시킨 뒤, X01 GBM 세포를 tMSLC-분비 ECM 조성물에 도말하였다. 48시간 후, 겔을 수직으로 절단하고, H&E 염색을 하여 상기 X01 GBM 세포의 침윤성을 시각화하였다. 침윤한 세포의 수를 웰당 세개의 현미경 필드로 계수하였다. tMSLC0903 was inoculated into the collagen matrix and cultured for 3 days to perform tMSLC0903-derived ECM remodeling. Thereafter, tMSLC0903 cells were killed using puromycin and X01 GBM cells were plated on tMSLC-secreted ECM compositions. After 48 hours, the gel was cut vertically and H & E stained to visualize the invasiveness of the X01 GBM cells. The number of infiltrated cells was counted in three microscope fields per well.
사이토카인 분석Cytokine analysis
인간 사이토카인 어레이 (Proteome Profiler Array Human Cytokine, R&D Systems, ARY005, Minneapolis, MN, USA)를 제조자의 지시 사항에 따라 수행하였다. 사이토카인의 발현 수준은 X-레이 필름으로 시각화하였고, 이미지 J 소프트웨어를 사용하여 밀도계로 양을 측정하였다. Human cytokine arrays (Proteome Profiler Array Human Cytokine, R & D Systems, ARY005, Minneapolis, MN, USA) were performed according to the manufacturer's instructions. The level of expression of cytokines was visualized as X-ray film and the amount was measured in the density meter using Image J software.
ELISAELISA
X101 GBM 세포 또는 tMSLCs를 도말하고 3일이 경과한 후 조정 배지(conditioned medium)를 회수하여, 그에 포함된 히알루론산의 양을 ELISA (human HA ELISA Kit, R&D Systems)로 측정하였다. X101 GBM cells or tMSLCs were plated and the conditioned medium was recovered after 3 days, and the amount of hyaluronic acid contained therein was measured by ELISA (human HA ELISA Kit, R & D Systems).
형질 주입(Transfusion transfectiontransfection ))
마이크로포레이터-미니 (Digital Bio Technology, Seoul, Korea)를 사용하여 세포에 siRNA를 형질 주입시켰다. 모든 siRNA는 Genolution Pharmaceuticals, Inc (Seoul, Korea)에서 구입하였다.SiRNA was transfected into cells using a microporous-mini (Digital Bio Technology, Seoul, Korea). All siRNAs were purchased from Genolution Pharmaceuticals, Inc (Seoul, Korea).
웨스턴Western 블럿Blot 분석(western blot analysis) Western blot analysis
프로테아즈 억제제(protease inhibitors)로 보충된 용해 완충액 (40 mM Tris-HCl (pH 8.0), 120 mM NaCl, 0.1% Nonidet-P40)을 사용하여 단백질을 추출함으로써 세포 용해물을 준비하였다. 단백질을 SDS-PAGE로 분리한 뒤, 니트로셀룰로오스 막 (Amersham, Arlington Heights, IL, USA)으로 이송시켰다. 상기 막을 트리스 생리 식염 완충액(Tris-buffered saline, TBS) 내에서 5% 무지방 분유로 블록한 뒤, 1차 항체와 함께 4℃에서 밤새 배양하였다. 페록시다제-컨쥬게이트 2차 항체를 사용하자 오염(blots)이 더욱 진해졌고, 단백질은 향상 화학 루미네센스(enhanced chemiluminescence, ECL)로 시각화하였다. Cell lysates were prepared by extracting proteins using lysis buffer (40 mM Tris-HCl (pH 8.0), 120 mM NaCl, 0.1% Nonidet-P40) supplemented with protease inhibitors. Proteins were separated by SDS-PAGE and transferred to a nitrocellulose membrane (Amersham, Arlington Heights, IL, USA). The membranes were blocked with 5% nonfat dry milk in Tris-buffered saline (TBS) and incubated overnight at 4 ° C with the primary antibody. Using the peroxidase-conjugated secondary antibody, the blots became more intense and the protein visualized with enhanced chemiluminescence (ECL).
RT-RT- PCRPCR
트리졸 (Invitrogen)을 사용하여 총 RNA를 분리한 뒤 SuperScript III First-Strand Synthesis SuperMix (Invitrogen)를 사용하여 역전사 하였다. 유전자 발현 수준은 PCR using Econo Taq Plus Green (Lucigen, Seoul, Korea)를 이용하여 분석하였고, 각 샘플마다 내부 통제로 β-액틴을 사용하였다. Total RNA was isolated using Trizol (Invitrogen) and then reverse transcribed using SuperScript III First-Strand Synthesis SuperMix (Invitrogen). Gene expression levels were analyzed by PCR using Econo Taq Plus Green (Lucigen, Seoul, Korea) and β-actin was used as an internal control for each sample.
통계적 분석Statistical analysis
모든 실험 데이터는 평균으로 나타내었고, 에러 막대는 표준 편차(standard deviation, SD)로 나타내었다. 다변량 분석을 위하여, 독립 표본 양측 스튜던트 테스트 (unpaired two-tailed Student's t-test) 또는 ANOVA을 이용하여 값들을 비교하였다. 모든 통계적 분석은 GraphPad Prism 7.0으로 수행하였고, p 값 <0.05 인 경우 유의한 것으로 판단하였다. All experimental data are presented as mean and error bars are expressed as standard deviation (SD). For multivariate analysis, values were compared using an unpaired two-tailed Student's t-test or ANOVA. All statistical analyzes were performed with GraphPad Prism 7.0 and were considered significant when p value <0.05.
ECM 미세 환경의 리모델링(remodeling)에 의한 By remodeling the ECM microenvironment tMSLCs의of tMSLCs GBMCPD 세포의 침윤성 증가 Increased cell invasion
GBM 세포의 침윤성에 tMSLCs가 미치는 영향을 확인하기 위하여, 트랜스 웰에 환자 유래 X01 GBM 세포와 tMSLC0903을 공동 배양하였다. 공동 배양 시, 도 1에서 보는 바와 같이, GBM 세포와 tMSLCs 사이에 공간을 두고 다공성 막을 통해 상호 소통(crosstalk)이 가능하도록 하였다. 공동 배양 후, 마트리겔로 전코팅된 트랜스웰을 사용하여 GBM 세포의 침윤성을 분석하였다. 도 2에서 보는 바와 같이, tMSLCs와의 공동 배양한 X01 GBM 세포의 침윤성이 단독 배양한 X01 GBM 세포보다 침윤성이 증가한 것을 볼 수 있었다. In order to confirm the effect of tMSLCs on the invasiveness of GBM cells, patient-derived X01 GBM cells and tMSLC0903 were co-cultured in transwells. In the co-culture, as shown in FIG. 1, a space between the GBM cells and the tMSLCs was allowed to crosstalk through the porous membrane. After co-culture, permeability of GBM cells was analyzed using transwells coated with Matrigel. As shown in FIG. 2, invasiveness of X01 GBM cells co-cultured with tMSLCs was more invasive than that of X01 GBM cells cultured alone.
또한, tMSLCs에 의해 조정된 ECM에서 GBM 세포의 침윤성을 분석하였다. 이를 위하여, 도 3에서 보는 바와 같이 성장 배지에 콜라겐 Ⅰ형과 마트리겔의 혼합물을 포함하는 Millicell 삽입물(inserts) 상에 tMSLCs를 도말한 뒤, 3일 동안 상기 세포가 ECM을 재조정 하도록 하였다. 이후, 퓨로마이신을 이용하여 모든 tMSLCs를 사멸시키고, 조정된 ECM을 남겨두었다. 상기 ECM 상에 X01 GBM 세포를 도말한 뒤, 겔 메트릭스를 수직으로 절편화한 후 헤마톡실린 및 에오신(H&E) 염색을 통하여 상기 X01 GBM 세포의 침윤성을 시각화 하였다. 그 결과 도 4에서 보는 바와 같이, tMSLCs에 의해 조정된 ECM에서 X01 GBM 세포는 대조군 ECM에 도말한 GBM 세포보다 침윤성이 증가한 것을 볼 수 있었다. 따라서, 상기 결과로부터 tMSLCs는 종양 미세 환경에서 세포 외 성분을 생산하여 GBM 세포의 침윤성을 증가시키는 것을 알 수 있다. We also analyzed the invasiveness of GBM cells in ECMs regulated by tMSLCs. For this, as shown in FIG. 3, tMSLCs were plated on Millicell inserts containing a mixture of collagen type I and matrigel in the growth medium, and the cells were allowed to readjust the ECM for 3 days. Thereafter, all tMSLCs were killed with puromycin and the conditioned ECM was left. After X01 GBM cells were plated on the ECM, the gel matrix was sectioned vertically, and the invasiveness of the X01 GBM cells was visualized by hematoxylin and eosin (H & E) staining. As a result, as shown in FIG. 4, in the ECM regulated by tMSLCs, X01 GBM cells showed increased invasiveness than GBM cells stained with control ECM. Thus, from the above results, it can be seen that tMSLCs produce extracellular components in the tumor microenvironment and increase invasiveness of GBM cells.
GBMCPD 미세 환경에서 In a microenvironment HAS2HAS2 유도를 통한 Through induction tMSLCs의of tMSLCs 히알루론산 생산 증가 Increased production of hyaluronic acid
반정량적 RT-PCR에 의하여, GBM 세포의 진행에 관여하는 ECM 성분의 발현 수준을 확인하였다. X01 GBM 세포와 tMSLCs에서 상기 ECM 성분의 발현량을 비교한 결과, GBM 세포와 비교하여 tMSLCs에서 히알루론산 합성 효소 2(HAS2)와 베르시칸(Versican, VCAN)의 발현량이 매우 높은 것을 확인할 수 있었다(도 5). 이에, 상기 tMSLCs에서 VCAN 또는 HAS2의 양을 대폭 감소시킨 후, GBM 세포와 공동 배양하여, 상기 GBM 세포의 이동 능력을 확인하였다. 상처 치유 분석 결과, 도 6에서 볼 수 있듯이, tMSLCs와 공동 배양한 X01 GBM 세포의 경우 단독으로 배양한 세포 보다 상처 부위를 채우기 위하여 빠르게 이동한 것을 볼 수 있으나, HAS2의 양을 감소시킨 경우 tMSLCs가 GBM 세포의 이동 능력에 영향을 미치지 않는 것을 볼 수 있었다. 마찬가지로, 도 7에서 보는 바와 같이, 트랜스웰에서 GBM 세포를 tMSLCs와 공동 배양하였을 때 세포 이동 능력이 증가하였으나, HAS2에 대한 소간섭 RNA(siRNA)를 형질 주입하자 그 효과가 감소한 것을 볼 수 있었다. By semi-quantitative RT-PCR, the level of expression of ECM components involved in the progression of GBM cells was confirmed. As a result of comparing the expression amounts of the ECM components in X01 GBM cells and tMSLCs, it was confirmed that the expression amounts of hyaluronic acid synthase 2 (HAS2) and Versican (VCAN) were very high in tMSLCs as compared to GBM cells (Fig. 5). After the amount of VCAN or HAS2 was significantly reduced in the tMSLCs, the GBM cells were co-cultured with the GBM cells to confirm the migration ability of the GBM cells. As shown in FIG. 6, in the case of X01 GBM cells co-cultured with tMSLCs, the cells migrated faster to fill the wound area than cells cultured alone. However, when the amount of HAS2 was decreased, tMSLCs GBM cells were not affected. Similarly, as shown in FIG. 7, when the GBM cells were co-cultured with the tMSLCs in the transwell, the cell migration ability was increased, but the effect of transfection of small interfering RNA (siRNA) to HAS2 was decreased.
이로부터 tMSLCs가 GBM 세포의 이주능을 증가시킴에 있어 HAS2가 중요한 역할을 하는 것을 알 수 있었다. From these results, it can be seen that HAS2 plays an important role in increasing the migration capability of GBM cells by tMSLCs.
한편, HAS2는 히알루론산 합성 반응에 있어서 속도 제한적 효소에 해당하므로, GBM 세포의 이동 능력에 대한 히알루론산의 영향을 평가하였다. 그 결과 도 8에서 보는 바와 같이, 히알루론산은 농도 의존적으로 GBM 세포의 이동 능력을 증가하는 것을 확인할 수 있었다. 또한, tMSLCs 및 GBM 세포로부터 얻어진 조정 배지(CM) 내 히알루론산의 함량을 분석한 결과, 도 9에서 보는 바와 같이, tMSLCs의 조정 배지 내 히알루론산의 함량이 GBM 세포의 조정 배지 내 히알루론산 함량보다 높을 것을 볼 수 있었다. 하지만, HAS2를 감소시킨 경우, HAS1 또는 HAS3를 감소시킨 경우와는 달리 tMSLCs의 조정 배지 내 히알루론산의 함량이 현저히 감소하였다(도 10). 또한, 도 11에서 보는 바와 같이, tMSLCs와 GBM 세포의 공동 배양 시 HAS2 수준은 증가하였으나, ELISA 분석 결과, 공동 배양 시 히알루론산의 함량 변화는 두드러지지 않았다(도 12). On the other hand, since HAS2 corresponds to a rate-limiting enzyme in hyaluronic acid synthesis reaction, the influence of hyaluronic acid on the migration ability of GBM cells was evaluated. As a result, as shown in FIG. 8, it was confirmed that hyaluronic acid increases the migration ability of GBM cells in a concentration-dependent manner. The content of hyaluronic acid in the control medium (CM) obtained from tMSLCs and GBM cells was analyzed. As shown in FIG. 9, the content of hyaluronic acid in the regulated medium of tMSLCs was lower than that of the regulated medium of GBM cells I could see that it was high. However, when HAS2 was reduced, the content of hyaluronic acid in the conditioned medium of the tMSLCs was markedly decreased (Fig. 10), unlike the case where HAS1 or HAS3 was decreased. Also, as shown in FIG. 11, HAS2 levels were increased during co-culture of tMSLCs and GBM cells, but ELISA analysis showed that the content of hyaluronic acid was not significantly changed during co-culture (FIG. 12).
이로부터 tMSLCs는 GBM 미세 환경에 있어서 HAS2를 통하여 히알루론산 풍부 ECM을 조성하는 것을 알 수 있었다. From these results, it was found that the tMSLCs form hyaluronic acid rich ECM through HAS2 in GBM microenvironment.
자가 분비를 통한 보충 인자 Supplementary factor through self-secretion C5a의C5a HAS2HAS2 유도 Judo
tMSLCs에서 HAS2를 조절하는 신호 메커니즘을 조사하기 위하여 사이토카인을 분석하였다. 그 결과 도 13에서 보는 바와 같이, tMSLCs와 GBM 세포에서 인터루킨-6(IL-6), 인터루킨-8(IL-8) 및 C5a가 다른 수준으로 발현되는 것을 확인할 수 있었다. 상기 인자들을 siRNA로 감소시킴으로써, tMSLCs에서 C5가 HAS2 유도에 중요한 역할을 하는 것을 알 수 있었다(도 14). 이와 함께, siRNA-중재 C5 감소는 tMSLCs에서 히알루론산의 생성을 감소시키는 것을 볼 수 있었다(도 15). 하지만, IL-6 또는 IL-8의 감소는 어떠한 영향도 미치지 않았다. Cytokines were analyzed to investigate signaling mechanisms that regulate HAS2 in tMSLCs. As a result, it was confirmed that IL-6 (IL-6), interleukin-8 (IL-8) and C5a were expressed at different levels in tMSLCs and GBM cells. By reducing these factors to siRNA, it was found that C5 plays an important role in HAS2 induction in tMSLCs (Fig. 14). In addition, siRNA-mediated C5 reduction was found to reduce the production of hyaluronic acid in tMSLCs (Fig. 15). However, the decrease in IL-6 or IL-8 had no effect.
또한, C5a 중화 항체를 처리하여 히알루론산 및 HAS2의 수준을 조사하였다. 그 결과, 도 16 및 17에서 보는 바와 같이, C5a에 대한 항체 처리 시 농도 의존적으로 히알루론산 및 HAS2의 발현 수준이 감소하는 것을 볼 수 있었다. tMSLCs에 의해 분비된 C5a는 수용체 C5aR1를 통하여 HAS2 발현을 유도하므로, siRNAs로 C5aR1를 감소시켜, 히알루론산 및 HAS2 발현 수준을 조사하였다. 도 18 및 19에서 보는 바와 같이, tMSLCs에서 C5aR1 넉다운 시 HAS2 및 히알루론산의 수준이 감소하는 것을 확인할 수 있었다. In addition, the level of hyaluronic acid and HAS2 was examined by treating the C5a neutralizing antibody. As a result, as shown in FIGS. 16 and 17, the level of hyaluronic acid and HAS2 expression was decreased in a concentration-dependent manner in antibody treatment with C5a. C5a secreted by tMSLCs induces HAS2 expression through receptor C5aR1, thus reducing C5aR1 with siRNAs and examining hyaluronic acid and HAS2 expression levels. As shown in FIGS. 18 and 19, it was confirmed that the levels of HAS2 and hyaluronic acid were decreased in C5aR1 knockdown in tMSLCs.
하지만, 도 20에서 보는 바와 같이, GBM 세포에 재조합 인간 C5a 단백질 (rh-C5a)을 첨가하여도 HAS2 발현 수준이 증가하지는 않았다. 이로부터 GBM 세포는 C5a에 대한 반응에 있어서 tMSLCs와는 근본적으로 다른 것을 알 수 있었다. However, as shown in Fig. 20, the addition of the recombinant human C5a protein (rh-C5a) to the GBM cells did not increase the HAS2 expression level. These results suggest that GBM cells are fundamentally different from tMSLCs in response to C5a.
이에, tMSLCs 및 GBM 세포에서 C5aR1의 수준을 확인한 결과, 도 21에서 보는 바와 같이, tMSLCs에서 C5aR1이 높게 발현되었으나, GBM 세포에서는 그 발현 수준이 tMSLCs에서 보다 현저히 낮은 것을 확인할 수 있었다. 이를 통하여 GBM 세포에 재조합 인간 C5a 단백질을 첨가하여도 HAS2 발현 수준에 변화가 없는 이유를 알 수 있었다. 다만, 상기 도 21에서 볼 수 있듯이, tMSLCs을 GBM과 공동 배양하여도, C5aR1 발현 수준이 증가하지 않는 것을 볼 수 있었다. As a result, the level of C5aR1 was observed in tMSLCs and GBM cells. As shown in FIG. 21, C5aR1 was highly expressed in tMSLCs, but the level of expression was significantly lower in GBM cells than in tMSLCs. This suggests that the addition of recombinant human C5a protein to GBM cells did not change HAS2 expression level. However, as shown in FIG. 21, even when co-cultured with GBM, tMSLCs did not increase C5aR1 expression level.
상기 결과를 고려하여, C5a 중화 항체를 처리하자 tMSLCs의 GBM 세포의 침윤성에 대한 영향이 농도 의존적으로 감소하는 것을 확인할 수 있었다(도 22 및 23). 따라서, 이러한 결과로부터 C5a는 tMSLCs에서 HAS2-중재 히알루론산 생산에 있어서 C5aR1에 대하여 리간드로서 역할을 수행하는 것을 알 수 있었다. Considering the above results, it was confirmed that the treatment of C5a neutralizing antibody reduced the effect of tMSLCs on the invasiveness of GBM cells in a concentration-dependent manner (FIGS. 22 and 23). Thus, from these results it can be seen that C5a acts as a ligand for C5aR1 in the production of HAS2-mediated hyaluronic acid in tMSLCs.
tMSLCs에서From tMSLCs ERKERK MAPK를MAPK 통한 through C5a의C5a HAS2HAS2 유도 Judo
tMSLCs에서 C5a에 대응하여 HAS2를 유도하는 신호의 중재 물질을 확인하기 위하여, tMSLCs에서 C5를 넉다운시킨 후, ERK, PI3K, JAK 및 STAT3를 포함하는 신호 물질들의 활성화 상태를 확인하였다. 도 24에서 보는 바와 같이, C5 siRNA를 처리하자 ERK MAPK가 억제되는 것을 확인할 수 있었다. 이와 함께, tMSLCs에서 MEK 억제제 U0126로 ERK 신호를 차단하자, qRT-PCR 결과 HAS2의 전사가 억제되었다(도 24). 하지만, PI3K, JAK 또는 STAT3 억제제를 처리한 경우, HAS2 전사에 아무런 영향을 미치지 않았다. 이와 마찬가지로 도 25에서 보는 바와 같이, ERK의 억제만이 히알루론산 생성을 감소시키는 것을 볼 수 있다. Activation of signal substances including ERK, PI3K, JAK and STAT3 was confirmed by knocking down C5 in tMSLCs to identify the interventional material of the signal that induced HAS2 in response to C5a in tMSLCs. As shown in FIG. 24, it was confirmed that ERK MAPK was inhibited by treating C5 siRNA. In addition, when the ERK signal was blocked by the MEK inhibitor U0126 in tMSLCs, the transcription of HAS2 was inhibited by qRT-PCR (Fig. 24). However, treatment with PI3K, JAK or STAT3 inhibitors had no effect on HAS2 transcription. Likewise, as shown in Fig. 25, it can be seen that suppression of ERK alone reduces hyaluronic acid production.
ERK가 히알루론산 생성에 중요한 역할을 하는 것임을 확인하기 위하여, tMSLCs에 MEK 억제제인 U0126 (0~15 μM)를 다양한 농도로 처리한 후 HAS2 및 히알루론산의 발현 수준을 분석하였다. 상기 결과와 마찬가지로 U0126을 처리하자 농도 의존적으로 HAS2 및 히알루론산의 발현이 감소하는 것을 확인할 수 있었다(도 26 및 27). To confirm that ERK plays an important role in the production of hyaluronic acid, tMSLCs were treated with various concentrations of the MEK inhibitor U0126 (0-15 μM), and the expression levels of HAS2 and hyaluronic acid were analyzed. As described above, U0126 treatment revealed that the expression of HAS2 and hyaluronic acid decreased in a concentration-dependent manner (FIGS. 26 and 27).
또한, C5a를 중화하는 항체를 처리하자 ERK1/2의 인산화를 억제하였으며(도 28), tMSLCs에서 ERK 억제는 공동 배양 시 tMSLCs가 X01 GBM 세포에 미치는 영향을 차단하는 것을 볼 수 있었다(도 29). In addition, treatment of antibodies neutralizing C5a inhibited phosphorylation of ERK1 / 2 (FIG. 28) and ERK inhibition in tMSLCs blocked the effects of tMSLCs on X01 GBM cells in co-culture (FIG. 29) .
상기 결과로부터, C5a는 tMSLCs에서 ERK MAPK 활성화를 통하여 HAS2를 유도함을 알 수 있다. From the above results, it can be seen that C5a induces HAS2 through activation of ERK MAPK in tMSLCs.
이상, 본 발명을 상기 실시 예를 중심으로 하여 설명하였으나 이는 예시에 지나지 아니하며, 본 발명은 본 발명의 기술분야에서 통상의 지식을 가진 자에게 자명한 다양한 변형 및 균등한 기타의 실시 예를 이하에 첨부한 청구범위 내에서 수행할 수 있다는 사실을 이해하여야 한다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.
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145 150 155 160 Val Trp Asp Gly Asn Tyr His Gln Pro Trp Glu Pro Ala Ala Ala Gly 165 170 175 Ala Val Gly Ala Gly Ala Tyr Arg Glu Val Glu Ala Glu Asp Pro Gly 180 185 190 Arg Leu Ala Val Glu Ala Leu Val Arg Thr Arg Arg Cys Val Cys Val 195 200 205 Ala Gln Arg Trp Gly Gly Lys Arg Glu Val Met Tyr Thr Ala Phe Lys 210 215 220 Ala Leu Gly Asp Ser Val Asp Tyr Val Gln Val Cys Asp Ser Asp Thr 225 230 235 240 Arg Leu Asp Pro Met Ala Leu Leu Glu Leu Val Arg Val Leu Asp Glu 245 250 255 Asp Pro Arg Val Gly Ala Val Gly Gly Asp Val Arg Ile Leu Asn Pro 260 265 270 Leu Asp Ser Trp Val Ser Phe Leu Ser Ser Leu Arg Tyr Trp Val Ala 275 280 285 Phe Asn Val Glu Arg Ala Cys Gln Ser Tyr Phe His Cys Val Ser Cys 290 295 300 Ile Ser Gly Pro Leu Gly Leu Tyr Arg Asn Asn Leu Leu Gln Gln Phe 305 310 315 320 Leu Glu Ala Trp Tyr Asn Gln Lys Phe Leu Gly Thr His Cys Thr Phe 325 330 335 Gly Asp Asp Arg His Leu Thr Asn Arg Met Leu Ser Met Gly Tyr Ala 340 345 350 Thr Lys Tyr Thr Ser Arg Ser Arg Cys Tyr Ser Glu Thr Pro Ser Ser 355 360 365 Phe Leu Arg Trp Leu Ser Gln Gln Thr Arg Trp Ser Lys Ser Tyr Phe 370 375 380 Arg Glu Trp Leu Tyr Asn Ala Leu Trp Trp His Arg His His Ala Trp 385 390 395 400 Met Thr Tyr Glu Ala Val Val Ser Gly Leu Phe Pro Phe Phe Val Ala 405 410 415 Ala Thr Val Leu Arg Leu Phe Tyr Ala Gly Arg Pro Trp Ala Leu Leu 420 425 430 Trp Val Leu Leu Cys Val Gln Gly Val Ala Leu Ala Lys Ala Ala Phe 435 440 445 Ala Ala Trp Leu Arg Gly Cys Leu Arg Met Val Leu Leu Ser Leu Tyr 450 455 460 Ala Pro Leu Tyr Met Cys Gly Leu Leu Pro Ala Lys Phe Leu Ala Leu 465 470 475 480 Val Thr Met Asn Gln Ser Gly Trp Gly Thr Ser Gly Arg Arg Lys Leu 485 490 495 Ala Ala Asn Tyr Val Pro Leu Leu Pro Leu Ala Leu Trp Ala Leu Leu 500 505 510 Leu Leu Gly Gly Leu Val Arg Ser Val Ala His Glu Ala Arg Ala Asp 515 520 525 Trp Ser Gly Pro Ser Arg Ala Ala Glu Ala Tyr His Leu Ala Ala Gly 530 535 540 Ala Gly Ala Tyr Val Gly Tyr Trp Val Ala Met Leu Thr Leu Tyr Trp 545 550 555 560 Val Gly Val Arg Arg Leu Cys Arg Arg Arg Thr Gly Gly Tyr Arg Val 565 570 575 Gln Val <210> 2 <211> 552 <212> PRT <213> Homo sapiens <400> 2 Met His Cys Glu Arg Phe Leu Cys Ile Leu Arg Ile Ile Gly Thr Thr 1 5 10 15 Leu Phe Gly Val Ser Leu Leu Leu Gly Ile Thr Ala Ala Tyr Ile Val 20 25 30 Gly Tyr Gln Phe Ile Gln Thr Asp Asn Tyr Tyr Phe Ser Phe Gly Leu 35 40 45 Tyr Gly Ala Phe Leu Ala Ser His Leu Ile Ile Gln Ser Leu Phe Ala 50 55 60 Phe Leu Glu His Arg Lys Met Lys Lys Ser Leu Glu Thr Pro Ile Lys 65 70 75 80 Leu Asn Lys Thr Val Ala Leu Cys Ile Ala Ala Tyr Gln Glu Asp Pro 85 90 95 Asp Tyr Leu Arg Lys Cys Leu Gln Ser Val Lys Arg Leu Thr Tyr Pro 100 105 110 Gly Ile Lys Val Val Met Val Ile Asp Gly Asn Ser Glu Asp Asp Leu 115 120 125 Tyr Met Met Asp Ile Phe Ser Glu Val Met Gly Arg Asp Lys Ser Ala 130 135 140 Thr Tyr Ile Trp Lys Asn Asn Phe His Glu Lys Gly Pro Gly Glu Thr 145 150 155 160 Asp Glu Ser His Lys Glu Ser Ser Gln His Val Thr Gln Leu Val Leu 165 170 175 Ser Asn Lys Ser Ile Cys Ile Met Gln Lys Trp Gly Gly Lys Arg Glu 180 185 190 Val Met Tyr Thr Ala Phe Arg Ala Leu Gly Arg Ser Val Asp Tyr Val 195 200 205 Gln Val Cys Asp Ser Asp Thr Met Leu Asp Pro Ala Ser Ser Val Glu 210 215 220 Met Val Lys Val Leu Glu Glu Asp Pro Met Val Gly Gly Val Gly Gly 225 230 235 240 Asp Val Gln Ile Leu Asn Lys Tyr Asp Ser Trp Ile Ser Phe Leu Ser 245 250 255 Ser Val Arg Tyr Trp Met Ala Phe Asn Ile Glu Arg Ala Cys Gln Ser 260 265 270 Tyr Phe Gly Cys Val Gln Cys Ile Ser Gly Pro Leu Gly Met Tyr Arg 275 280 285 Asn Ser Leu Leu His Glu Phe Val Glu Asp Trp Tyr Asn Gln Glu Phe 290 295 300 Met Gly Asn Gln Cys Ser Phe Gly Asp Asp Arg His Leu Thr Asn Arg 305 310 315 320 Val Leu Ser Leu Gly Tyr Ala Thr Lys Tyr Thr Ala Arg Ser Lys Cys 325 330 335 Leu Thr Glu Thr Pro Ile Glu Tyr Leu Arg Trp Leu Asn Gln Gln Thr 340 345 350 Arg Trp Ser Lys Ser Tyr Phe Arg Glu Trp Leu Tyr Asn Ala Met Trp 355 360 365 Phe His Lys His His Leu Trp Met Thr Tyr Glu Ala Ile Ile Thr Gly 370 375 380 Phe Phe Pro Phe Phe Leu Ile Ala Thr Val Ile Gln Leu Phe Tyr Arg 385 390 395 400 Gly Lys Ile Trp Asn Ile Leu Leu Phe Leu Leu Thr Val Gln Leu Val 405 410 415 Gly Leu Ile Lys Ser Ser Phe Ala Ser Cys Leu Arg Gly Asn Ile Val 420 425 430 Met Val Phe Met Ser Leu Tyr Ser Val Leu Tyr Met Ser Ser Leu Leu 435 440 445 Pro Ala Lys Met Phe Ala Ile Ala Thr Ile Asn Lys Ala Gly Trp Gly 450 455 460 Thr Ser Gly Arg Lys Thr Ile Val Val Asn Phe Ile Gly Leu Ile Pro 465 470 475 480 Val Ser Val Trp Phe Thr Ile Leu Leu Gly Gly Val Ile Phe Thr Ile 485 490 495 Tyr Lys Glu Ser Lys Arg Pro Phe Ser Glu Ser Lys Gln Thr Val Leu 500 505 510 Ile Val Gly Thr Leu Leu Tyr Ala Cys Tyr Trp Val Met Leu Leu Thr 515 520 525 Leu Tyr Val Val Leu Ile Asn Lys Cys Gly Arg Arg Lys Lys Gly Gln 530 535 540 Gln Tyr Asp Met Val Leu Asp Val 545 550 <210> 3 <211> 553 <212> PRT <213> Homo sapiens <400> 3 Met Pro Val Gln Leu Thr Thr Ala Leu Arg Val Val Gly Thr Ser Leu 1 5 10 15 Phe Ala Leu Ala Val Leu Gly Gly Ile Leu Ala Ala Tyr Val Thr Gly 20 25 30 Tyr Gln Phe Ile His Thr Glu Lys His Tyr Leu Ser Phe Gly Leu Tyr 35 40 45 Gly Ala Ile Leu Gly Leu His Leu Leu Ile Gln Ser Leu Phe Ala Phe 50 55 60 Leu Glu His Arg Arg Met Gln Arg Ala Gly Gln Ala Leu Lys Leu Pro 65 70 75 80 Ser Pro Arg Arg Gly Ser Val Ala Leu Cys Ile Ala Ala Tyr Gln Glu 85 90 95 Asp Pro Asp Tyr Leu Arg Lys Cys Leu Arg Ser Ala Gln Arg Ile Ser 100 105 110 Phe Pro Asp Leu Lys Val Val Met Val Val Asp Gly Asn Arg Gln Glu 115 120 125 Asp Ala Tyr Met Leu Asp Ile Phe His Glu Val Leu Gly Gly Thr Glu 130 135 140 Gln Ala Gly Phe Phe Val Trp Arg Ser Asn Phe His Glu Ala Gly Glu 145 150 155 160 Gly Glu Thr Glu Ala Ser Leu Gln Glu Gly Met Asp Arg Val Arg Asp 165 170 175 Val Val Arg Ala Ser Thr Phe Ser Cys Ile Met Gln Lys Trp Gly Gly 180 185 190 Lys Arg Glu Val Met Tyr Thr Ala Phe Lys Ala Leu Gly Asp Ser Val 195 200 205 Asp Tyr Ile Gln Val Cys Asp Ser Asp Thr Val Leu Asp Pro Ala Cys 210 215 220 Thr Ile Glu Met Leu Arg Val Leu Glu Glu Asp Pro Gln Val Gly Gly 225 230 235 240 Val Gly Gly Asp Val Gln Ile Leu Asn Lys Tyr Asp Ser Trp Ile Ser 245 250 255 Phe Leu Ser Ser Val Arg Tyr Trp Met Ala Phe Asn Val Glu Arg Ala 260 265 270 Cys Gln Ser Tyr Phe Gly Cys Val Gln Cys Ile Ser Gly Pro Leu Gly 275 280 285 Met Tyr Arg Asn Ser Leu Leu Gln Gln Phe Leu Glu Asp Trp Tyr His 290 295 300 Gln Lys Phe Leu Gly Ser Lys Cys Ser Phe Gly Asp Asp Arg His Leu 305 310 315 320 Thr Asn Arg Val Leu Ser Leu Gly Tyr Arg Thr Lys Tyr Thr Ala Arg 325 330 335 Ser Lys Cys Leu Thr Glu Thr Pro Thr Lys Tyr Leu Arg Trp Leu Asn 340 345 350 Gln Gln Thr Arg Trp Ser Lys Ser Tyr Phe Arg Glu Trp Leu Tyr Asn 355 360 365 Ser Leu Trp Phe His Lys His His Leu Trp Met Thr Tyr Glu Ser Val 370 375 380 Val Thr Gly Phe Phe Pro Phe Phe Leu Ile Ala Thr Val Ile Gln Leu 385 390 395 400 Phe Tyr Arg Gly Arg Ile Trp Asn Ile Leu Leu Phe Leu Leu Thr Val 405 410 415 Gln Leu Val Gly Ile Ile Lys Ala Thr Tyr Ala Cys Phe Leu Arg Gly 420 425 430 Asn Ala Glu Met Ile Phe Met Ser Leu Tyr Ser Leu Leu Tyr Met Ser 435 440 445 Ser Leu Leu Pro Ala Lys Ile Phe Ala Ile Ala Thr Ile Asn Lys Ser 450 455 460 Gly Trp Gly Thr Ser Gly Arg Lys Thr Ile Val Val Asn Phe Ile Gly 465 470 475 480 Leu Ile Pro Val Ser Ile Trp Val Ala Val Leu Leu Gly Gly Leu Ala 485 490 495 Tyr Thr Ala Tyr Cys Gln Asp Leu Phe Ser Glu Thr Glu Leu Ala Phe 500 505 510 Leu Val Ser Gly Ala Ile Leu Tyr Gly Cys Tyr Trp Val Ala Leu Leu 515 520 525 Met Leu Tyr Leu Ala Ile Ile Ala Arg Arg Cys Gly Lys Lys Pro Glu 530 535 540 Gln Ser Ser Leu Ala Phe Ala Glu Val 545 550 <110> Industry-Academic Cooperation Foundation, Yonsei University <120> Method for screening metastasis inhibitor for cancer <130> DPB167251.k01 <150> KR 16/0153553 <151> 2016-11-17 <160> 3 <170> KoPatentin 3.0 <210> 1 <211> 578 <212> PRT <213> Homo sapiens <400> 1 Met Arg Gln Gln Asp Ala Pro Lys Pro Thr Pro Ala Ala Cys Arg Cys 1 5 10 15 Ser Gly Leu Ala Arg Arg Val Leu Thr Ile Ala Phe Ala Leu Leu Ile 20 25 30 Leu Gly Leu Met Thr Trp Ala Tyr Ala 35 40 45 Asp Arg Tyr Gly Leu Leu Ala Phe Gly Leu Tyr Gly Ala Phe Leu Ser 50 55 60 Ala His Leu Val Ala Gln Ser Leu Phe Ala Tyr Leu Glu His Arg Arg 65 70 75 80 Val Ala Ala Ala Ala Arg Gly Pro Leu Asp Ala Ala Thr Ala Arg Ser 85 90 95 Val Ala Leu Thr Ile Ser Ala Tyr Gln Glu Asp Pro Ala Tyr Leu Arg 100 105 110 Gln Cys Leu Ala Ser Ala Arg Ala Leu Leu Tyr Pro Arg Ala Arg Leu 115 120 125 Arg Val Leu Met Val Val Asp Gly Asn Arg Ala Glu Asp Leu Tyr Met 130 135 140 Val Asp Met Phe Arg Glu Val Phe Ala Asp Glu Asp Pro Ala Thr Tyr 145 150 155 160 Val Trp Asp Gly Asn Tyr His Gln Pro Trp Glu Pro Ala Ala Ala Gly 165 170 175 Ala Val Gly Ala Gly Ala Tyr Arg Glu Val Glu Ala Glu Asp Pro Gly 180 185 190 Arg Leu Ala Val Glu Ala Leu Val Arg Thr Arg Arg Cys Val Cys Val 195 200 205 Ala Gln Arg Trp Gly Gly Lys Arg Glu Val Met Tyr Thr Ala Phe Lys 210 215 220 Ala Leu Gly Asp Ser Val Asp Tyr Val Gln Val Cys Asp Ser Asp Thr 225 230 235 240 Arg Leu Asp Pro Met Ala Leu Leu Leu Val Val Leu Asp Glu 245 250 255 Asp Pro Arg Val Gly Ala Val Gly Gly Asp Val Arg Ile Leu Asn Pro 260 265 270 Leu Asp Ser Trp Val Ser Phe Leu Ser Ser Leu Arg Tyr Trp Val Ala 275 280 285 Phe Asn Val Glu Arg Ala Cys Gln Ser Tyr Phe His Cys Val Ser Cys 290 295 300 Ile Ser Gly Pro Leu Gly Leu Tyr Arg Asn Asn Leu Leu Gln Gln Phe 305 310 315 320 Leu Glu Ala Trp Tyr Asn Gln Lys Phe Leu Gly Thr His Cys Thr Phe 325 330 335 Gly Asp Asp Arg His Leu Thr Asn Arg Met Leu Ser Met Gly Tyr Ala 340 345 350 Thr Lys Tyr Thr Ser Ser Ser Ser Cys Tyr Ser Glu Thr Ser Ser Ser 355 360 365 Phe Leu Arg Trp Leu Ser Gln Gln Thr Arg Trp Ser Lys Ser Tyr Phe 370 375 380 Arg Glu Trp Leu Tyr Asn Ala Leu Trp Trp His Arg His His Ala Trp 385 390 395 400 Met Thr Tyr Glu Ala Val Val Ser Gly Leu Phe Pro Phe Phe Val Ala 405 410 415 Ala Thr Val Leu Arg Leu Phe Tyr Ala Gly Arg Pro Trp Ala Leu Leu 420 425 430 Trp Val Leu Leu Cys Val Gln Gly Val Ala Leu Ala Lys Ala Ala Phe 435 440 445 Ala Ala Trp Leu Arg Gly Cys Leu Arg Met Val Leu Leu Ser Leu Tyr 450 455 460 Ala Pro Leu Tyr Met Cys Gly Leu Leu Pro Ala Lys Phe Leu Ala Leu 465 470 475 480 Val Thr Met Asn Gln Ser Gly Trp Gly Thr Ser Gly Arg Arg Lys Leu 485 490 495 Ala Ala Asn Tyr Val Leu Leu Pro Leu Ala Leu Trp Ala Leu Leu 500 505 510 Leu Leu Gly Gly Leu Val Arg Ser Val Ala His Glu Ala Arg Ala Asp 515 520 525 Trp Ser Gly Pro Ser Arg Ala Ala Glu Ala Tyr His Leu Ala Ala Gly 530 535 540 Ala Gly Ala Tyr Val Gly Tyr Trp Val Ala Met Leu Thr Leu Tyr Trp 545 550 555 560 Val Gly Val Arg Arg Leu Cys Arg Arg Arg Thr Gly Gly Tyr Arg Val 565 570 575 Gln Val <210> 2 <211> 552 <212> PRT <213> Homo sapiens <400> 2 Met His Cys Glu Arg Phe Leu Cys Ile Leu Arg Ile Ile Gly Thr Thr 1 5 10 15 Leu Phe Gly Val Ser Leu Leu Le Gly Ile Thr Ala Ala Tyr Ile Val 20 25 30 Gly Tyr Gln Phe Ile Gln Thr Asp Asn Tyr Tyr Phe Ser Phe Gly Leu 35 40 45 Tyr Gly Ala Phe Leu Ala Ser His Leu Ile Ile Gln Ser Leu Phe Ala 50 55 60 Phe Leu Glu His Arg Lys Met Lys Lys Ser Leu Glu Thr Pro Ile Lys 65 70 75 80 Leu Asn Lys Thr Val Ala Leu Cys Ile Ala Ala Tyr Gln Glu Asp Pro 85 90 95 Asp Tyr Leu Arg Lys Cys Leu Gln Ser Val Lys Arg Leu Thr Tyr Pro 100 105 110 Gly Ile Lys Val Val Met Valle Asp Gly Asn Ser Glu Asp Asp Leu 115 120 125 Tyr Met Met Asp Ile Phe Ser Glu Val Met Gly Arg Asp Lys Ser Ala 130 135 140 Thr Tyr Ile Trp Lys Asn Asn Phe His Glu Lys Gly Pro Gly Glu Thr 145 150 155 160 Asp Glu Ser His Lys Glu Ser Ser Gln His Val Thr Gln Leu Val Leu 165 170 175 Ser Asn Lys Ser Ile Cys Ile Met Gln Lys Trp Gly Gly Lys Arg Glu 180 185 190 Val Met Tyr Thr Ala Phe Arg Ala Leu Gly Arg Ser Val Asp Tyr Val 195 200 205 Gln Val Cys Asp Ser Asp Thr Met Leu Asp Pro Ala Ser Ser Val Glu 210 215 220 Met Val Lys Val Leu Glu Glu Asp Pro Met Val Gly Gly Val Gly Gly 225 230 235 240 Asp Val Gln Ile Leu Asn Lys Tyr Asp Ser Trp Ile Ser Phe Leu Ser 245 250 255 Ser Val Arg Tyr Trp Met Ala Phe Asn Ile Glu Arg Ala Cys Gln Ser 260 265 270 Tyr Phe Gly Cys Val Gln Cys Ile Ser Gly Pro Leu Gly Met Tyr Arg 275 280 285 Asn Ser Leu Leu His Glu Phe Val Glu Asp Trp Tyr Asn Gln Glu Phe 290 295 300 Met Gly Asn Gln Cys Ser Phe Gly Asp Asp Arg His Leu Thr Asn Arg 305 310 315 320 Val Leu Ser Leu Gly Tyr Ala Thr Lys Tyr Thr Ala Arg Ser Lys Cys 325 330 335 Leu Thr Glu Thr Pro Ile Glu Tyr Leu Arg Trp Leu Asn Gln Gln Thr 340 345 350 Arg Trp Ser Lys Ser Tyr Phe Arg Glu Trp Leu Tyr Asn Ala Met Trp 355 360 365 Phe His Lys His His Leu Trp Met Thr Tyr Glu Ala Ile Ile Thr Gly 370 375 380 Phe Phe Pro Phe Phe Leu Phe Tyr Arg 385 390 395 400 Gly Lys Ile Trp Asn Ile Leu Leu Phe Leu Leu Thr Val Gln Leu Val 405 410 415 Gly Leu Ile Lys Ser Ser Phe Ala Ser Cys Leu Arg Gly Asn Ile Val 420 425 430 Met Val Phe Met Ser Leu Tyr Ser Val Leu Tyr Met Ser Ser Leu Leu 435 440 445 Pro Ala Lys Met Phe Ala Ile Ala Thr Ile Asn Lys Ala Gly Trp Gly 450 455 460 Thr Ser Gly Arg Lys Thr Ile Val Val Asn Phe Ile Gly Leu Ile Pro 465 470 475 480 Val Ser Val Trp Phe Thr Ile Leu Leu Gly Gly Val Ile Phe Thr Ile 485 490 495 Tyr Lys Glu Ser Lys Arg Pro Phe Ser Glu Ser Lys Gln Thr Val Leu 500 505 510 Ile Val Gly Thr Leu Leu Tyr Ala Cys Tyr Trp Val Met Leu Leu Thr 515 520 525 Leu Tyr Val Val Leu Ile Asn Lys Cys Gly Arg Arg Lys Lys Gly Gln 530 535 540 Gln Tyr Asp Met Val Leu Asp Val 545 550 <210> 3 <211> 553 <212> PRT <213> Homo sapiens <400> 3 Met Pro Val Gln Leu Thr Thr Ala Leu Arg Val Val Gly Thr Ser Leu 1 5 10 15 Phe Ala Leu Ala Val Leu Gly Gly Ile Leu Ala Ala Tyr Val Thr Gly 20 25 30 Tyr Gln Phe Ile His Thr Glu Lys His Tyr Leu Ser Phe Gly Leu Tyr 35 40 45 Gly Ala Ile Leu Gly Leu His Leu Leu Ile Gln Ser Leu Phe Ala Phe 50 55 60 Leu Glu His Arg Arg Met Gln Arg Ala Gly Gln Ala Leu Lys Leu Pro 65 70 75 80 Ser Pro Arg Gly Ser Val Ala Leu Cys Ile Ala Ala Tyr Gln Glu 85 90 95 Asp Pro Asp Tyr Leu Arg Lys Cys Leu Arg Ser Ala Gln Arg Ile Ser 100 105 110 Phe Pro Asp Leu Lys Val Val Met Val Val Asp Gly Asn Arg Gln Glu 115 120 125 Asp Ala Tyr Met Leu Asp Ile Phe His Glu Val Leu Gly Gly Thr Glu 130 135 140 Gln Ala Gly Phe Phe Val Trp Arg Ser Asn Phe His Glu Ala Gly Glu 145 150 155 160 Gly Glu Thr Glu Ala Ser Leu Gln Glu Gly Met Asp Arg Val Val Asp 165 170 175 Val Val Arg Ala Ser Thr Phe Ser Cys Ile Met Gln Lys Trp Gly Gly 180 185 190 Lys Arg Glu Val Met Tyr Thr Ala Phe Lys Ala Leu Gly Asp Ser Val 195 200 205 Asp Tyr Ile Gln Val Cys Asp Ser Asp Thr Val Leu Asp Pro Ala Cys 210 215 220 Thr Ile Glu Met Leu Arg Val Leu Glu Glu Asp Pro Gln Val Gly Gly 225 230 235 240 Val Gly Gly Asp Val Gln Ile Leu Asn Lys Tyr Asp Ser Trp Ile Ser 245 250 255 Phe Leu Ser Ser Val Arg Tyr Trp Met Ala Phe Asn Val Glu Arg Ala 260 265 270 Cys Gln Ser Tyr Phe Gly Cys Val Gln Cys Ile Ser Gly Pro Leu Gly 275 280 285 Met Tyr Arg Asn Ser Leu Leu Gln Gln Phe Leu Glu Asp Trp Tyr His 290 295 300 Gln Lys Phe Leu Gly Ser Lys Cys Ser Phe Gly Asp Asp Arg His Leu 305 310 315 320 Thr Asn Arg Val Leu Ser Leu Gly Tyr Arg Thr Lys Tyr Thr Ala Arg 325 330 335 Ser Lys Cys Leu Thr Glu Thr Pro Thr Lys Tyr Leu Arg Trp Leu Asn 340 345 350 Gln Gln Thr Arg Trp Ser Lys Ser Tyr Phe Arg Glu Trp Leu Tyr Asn 355 360 365 Ser Leu Trp Phe His Lys His His Leu Trp Met Thr Tyr Glu Ser Val 370 375 380 Val Thr Gly Phe Phe Pro Phe Phe Leu Ile Ala Thr Val Ile Gln Leu 385 390 395 400 Phe Tyr Arg Gly Arg Ile Trp Asn Ile Leu Leu Phe Leu Leu Thr Val 405 410 415 Gln Leu Val Gly Ile Ile Lys Ala Thr Tyr Ala Cys Phe Leu Arg Gly 420 425 430 Asn Ala Glu Met Ile Phe Met Ser Leu Tyr Ser Leu Leu Tyr Met Ser 435 440 445 Ser Leu Leu Pro Ala Lys Ile Phe Ala Ile Ala Thr Ile Asn Lys Ser 450 455 460 Gly Trp Gly Thr Ser Gly Arg Lys Thr Ile Val Val Asn Phe Ile Gly 465 470 475 480 Leu Ile Pro Val Ser Ile Trp Val Ala Val Leu Leu 485 490 495 Tyr Thr Ala Tyr Cys Gln Asp Leu Phe Ser Glu Thr Glu Leu Ala Phe 500 505 510 Leu Val Ser Gly Ala Ile Leu Tyr Gly Cys Tyr Trp Val Ala Leu Leu 515 520 525 Met Leu Tyr Leu Ala Ile Ile Ala Arg Arg Cys Gly Lys Lys Pro Glu 530 535 540 Gln Ser Ser Leu Ala Phe Ala Glu Val 545 550
Claims (13)
(b) 분리된 암-간엽 줄기 유사 세포에 약물을 처리하는 단계;
(c) 상기 약물이 처리된 암-간엽 줄기 유사 세포의 히알루론산 합성 효소(Hyaluronic acid synthase, HAS) 또는 이를 코딩하는 mRNA의 발현 수준을 측정하는 단계; 및
(d) 상기 암-간엽 줄기 유사 세포의 히알루론산 합성 효소의 발현 수준이 약물 처리 전에 비하여 감소된 경우, 상기 약물을 암 전이 억제제 후보물질로 판단하는 단계를 포함하는 암 전이 억제제의 스크리닝 방법.(a) isolating cancer-stem cell-like cells from a cancer patient;
(b) treating the drug with isolated cancer-mesenchymal stem cells;
(c) measuring the expression level of hyaluronic acid synthase (HAS) of the cancer-mesenchymal stem cell-like cell treated with the drug or the mRNA encoding the same; And
(d) judging the drug as a cancer metastasis inhibitor candidate when the expression level of hyaluronic acid synthase in the cancer-mesenchymal stem cell-like cells is decreased as compared with that before drug treatment.
상기 히알루론산 합성 효소는 히알루론산 합성 효소 2인, 암 전이 억제제의 스크리닝 방법.The method according to claim 1,
Wherein said hyaluronic acid synthetase is a hyaluronic acid synthase 2, screening method for inhibiting cancer metastasis.
상기 암은 뇌암, 폐암, 비소세포성폐암, 결장암, 골암, 췌장암, 피부암, 두부 또는 경부 암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS; central nervous system) 종양, 1차 CNS 림프종, 척수 종양, 및 뇌하수체 선종으로 이루어진 군에서 선택되는, 암 전이 억제제의 스크리닝 방법.The method according to claim 1,
Wherein the cancer is selected from the group consisting of brain cancer, lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, Cancer, endometrioid cancer, thyroid cancer, pituitary cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, uterine cancer, endometrial carcinoma, endometrial cancer, uterine cancer, vulvar carcinoma, vulvar carcinoma, Hodgkin's disease, (CNS) tumors, primary CNS lymphoma, spinal cord tumors, and pituitary adenomas. The present invention also relates to the use of a compound of the present invention for the manufacture of a medicament for the treatment or prophylaxis of cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, ≪ / RTI >
상기 암은 뇌암인, 암 전이 억제제의 스크리닝 방법.The method according to claim 1,
Wherein the cancer is brain cancer.
상기 히알루론산 합성 효소의 발현 수준은 방사능 면역 분석, 방사능 면역 침전, 면역 침전, ELISA(enzyme-linked immunosorbentassay), 캡처-ELISA, 억제 또는 경재 분석, 및 샌드위치 분석으로 이루어진 군에서 선택되는 면역 분석 방법으로 측정되는, 암 전이 억제제의 스크리닝 방법.The method according to claim 1,
The expression level of the hyaluronic acid synthetase is determined by radioimmunoassay, radioimmunoprecipitation, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), capture-ELISA, inhibition or hardwood analysis, and sandwich assay ≪ / RTI >
상기 히알루론산 합성 효소를 코딩하는 mRNA의 발현 수준은 중합효소연쇄반응(PCR), 역전사 중합효소연쇄반응(RT-PCR), 실시간 중합효소연쇄반응(Real-time PCR), RNase 보호 분석법(RNase protection assay; RPA), 마이크로어레이(microarray), 및 노던 블롯팅(northern blotting)으로 이루어진 군으로부터 선택되는 방법으로 측정되는, 암 전이 억제제의 스크리닝 방법.The method according to claim 1,
The expression level of mRNA encoding the hyaluronic acid synthase can be determined by PCR, reverse transcription polymerase chain reaction (RT-PCR), real-time PCR, RNase protection assay, RPA), microarray, and northern blotting. The method of screening for cancer metastasis inhibitors according to claim 1, wherein the cancer is selected from the group consisting of RPA, microarray, and northern blotting.
상기 (b) 단계에서 약물 처리 시 항암제를 추가로 처리하는, 암 전이 억제제의 스크리닝 방법.The method according to claim 1,
The method for screening cancer metastasis inhibitor according to any one of claims 1 to 3, wherein the cancer treatment agent is further treated during drug treatment in step (b).
상기 항암제는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상인, 암 전이 억제제의 스크리닝 방법.8. The method of claim 7,
Wherein the anticancer agent is selected from the group consisting of nitrogene mustard, imatinib, oxaliplatin, rituximab, elotinib, neratib, lapatinib, zetitnib, vanadate, nilotinib, semathanib, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, Amlodipine, amlasturamine, amlastuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, amlodipine, amlodipine, But are not limited to, doxifluridine, femetrexed, tegafur, capecitabine, gimeracin, atheracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, , Decitabine, mercaptofu But are not limited to, rhein, thioguanine, cladribine, calmophor, ralitriptycde, docetaxel, paclitaxel, irinotecan, velotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, But are not limited to, psoriasis, psoriasis, epidermidis, psoriasis, epirubicin, mitoxantrone, mitomycin, blormomycin, daunorubicin, dactinomycin, pyrabicin, aclarubicin, pepromycin, temesolorimus, temozolomide, But are not limited to, but are not limited to, aminoglutethimide, spearmade, cyclophosphamide, melphalan, altretin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, reucoborin, tretonin, Wherein the cancer metastasis inhibitor is at least one selected from the group consisting of atorvastatin, atorvastatin, atorvastatin, atorvastatin, atorvastatin, atorvastatin, atorvastatin, atorvastatin, Screening method .
(2) 분리된 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2(Hyaluronic acid synthase 2, HAS 2)와, 히알루론산 합성 효소 1(Hyaluronic acid synthase 1, HAS 1) 및 히알루론산 합성 효소 3(Hyaluronic acid synthase 3, HAS 3) 중 적어도 하나의 단백질 또는 이를 코딩하는 mRNA의 발현 수준을 측정하는 단계; 및
(3) 상기 암-간엽 줄기 유사 세포의 히알루론산 합성 효소 2 또는 이를 코딩하는 mRNA의 발현 수준이 상기 히알루론산 합성 효소 1 및 상기 히알루론산 합성 효소 3 중 적어도 하나의 단백질 또는 이를 코딩하는 mRNA의 발현 수준보다 높은 경우, 암의 전이 가능성이 높은 것으로 판단하는 단계를 포함하는, 암의 전이 가능성 예측에 대한 정보 제공 방법.(1) separating cancer-stem cell-like cells from cancer patients;
(2) Hyaluronic acid synthase 2 (HAS 2), hyaluronic acid synthase 1 (HAS 1) and hyaluronic acid synthase 3 (Hyaluronic acid synthase 1) of isolated cancer-mesenchymal stem cells acid synthase 3, HAS 3) or an mRNA encoding the protein or at least one protein thereof; And
(3) the expression level of the hyaluronic acid synthase 2 or the mRNA encoding the hyaluronan synthase 2 or the hyaluronan synthase 3 of the cancer-mesenchymatoid stem cell is at least one of the expression of the hyaluronan synthase 1 and the hyaluronan synthase 3 or the expression of the mRNA encoding the same Determining that cancer is more likely to metastasise if the cancer is at a higher level.
상기 암은 뇌암, 폐암, 비소세포성폐암, 결장암, 골암, 췌장암, 피부암, 두부 또는 경부 암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS; central nervous system) 종양, 1차 CNS 림프종, 척수 종양, 및 뇌하수체 선종으로 이루어진 군에서 선택되는, 암의 전이 가능성 예측에 대한 정보 제공 방법.10. The method of claim 9,
Wherein the cancer is selected from the group consisting of brain cancer, lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, Cancer, endometrioid cancer, thyroid cancer, pituitary cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, uterine cancer, endometrial carcinoma, endometrial cancer, uterine cancer, vulvar carcinoma, vulvar carcinoma, Hodgkin's disease, (CNS) tumors, primary CNS lymphoma, spinal cord tumors, and pituitary adenomas. The present invention also relates to the use of a compound of the present invention for the manufacture of a medicament for the treatment or prophylaxis of cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, Wherein the cancer is selected from the group consisting of:
상기 암은 뇌암인, 암의 전이 가능성 예측에 대한 정보 제공 방법.10. The method of claim 9,
Wherein said cancer is brain cancer.
상기 히알루론산 합성 효소 1, 상기 히알루론산 합성 효소 2 또는 상기 히알루론산 합성 효소 3의 발현 수준은 방사능 면역 분석, 방사능 면역 침전, 면역 침전, ELISA(enzyme-linked immunosorbentassay), 캡처-ELISA, 억제 또는 경재 분석, 및 샌드위치 분석으로 이루어진 군에서 선택되는 면역 분석 방법으로 측정되는, 암의 전이 가능성 예측에 대한 정보 제공 방법.10. The method of claim 9,
The expression levels of hyaluronic acid synthase 1, hyaluronan synthase 2 or hyaluronate synthase 3 may be determined by radioimmunoassay, radioimmunoprecipitation, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), capture-ELISA, Analysis, and sandwich analysis, as measured by an immunoassay method selected from the group consisting of:
상기 히알루론산 합성 효소 1, 상기 히알루론산 합성 효소 2 또는 상기 히알루론산 합성 효소 3를 코딩하는 mRNA의 발현 수준은 중합효소연쇄반응(PCR), 역전사 중합효소연쇄반응(RT-PCR), 실시간 중합효소연쇄반응(Real-time PCR), RNase 보호 분석법(RNase protection assay; RPA), 마이크로어레이(microarray), 및 노던 블롯팅(northern blotting)으로 이루어진 군으로부터 선택되는 방법으로 측정되는, 암의 전이 가능성 예측에 대한 정보 제공 방법.10. The method of claim 9,
The expression level of the hyaluronan synthase 1, the hyaluronan synthase 2 or the hyaluronan synthase 3 may be determined by PCR, reverse transcription polymerase chain reaction (RT-PCR), real-time PCR The predictability of cancer metastasis, as measured by a method selected from the group consisting of real-time PCR, RNase protection assay (RPA), microarray, and northern blotting / RTI >
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003289748A (en) * | 2001-06-27 | 2003-10-14 | Takeda Chem Ind Ltd | Method for preparation of model animal of arthropathy |
US20060147453A1 (en) * | 2002-06-29 | 2006-07-06 | Genentech, Inc. | Methods and compositions for modulating and detecting WISP activity |
JP2012519730A (en) * | 2009-07-06 | 2012-08-30 | アケビア セラピューティクス インコーポレイテッド | Compounds, compositions and methods for preventing metastasis of cancer cells |
KR101213033B1 (en) * | 2011-08-23 | 2012-12-18 | 연세대학교 산학협력단 | Diagnostic kit for cancer metastasis and method of providing the informaion for diagnosis of cancer metastasis |
JP2015533796A (en) * | 2012-09-07 | 2015-11-26 | トラスティーズ・オブ・ダートマス・カレッジ | VISTA modulators for cancer diagnosis and treatment |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003289748A (en) * | 2001-06-27 | 2003-10-14 | Takeda Chem Ind Ltd | Method for preparation of model animal of arthropathy |
US20060147453A1 (en) * | 2002-06-29 | 2006-07-06 | Genentech, Inc. | Methods and compositions for modulating and detecting WISP activity |
JP2012519730A (en) * | 2009-07-06 | 2012-08-30 | アケビア セラピューティクス インコーポレイテッド | Compounds, compositions and methods for preventing metastasis of cancer cells |
KR101213033B1 (en) * | 2011-08-23 | 2012-12-18 | 연세대학교 산학협력단 | Diagnostic kit for cancer metastasis and method of providing the informaion for diagnosis of cancer metastasis |
JP2015533796A (en) * | 2012-09-07 | 2015-11-26 | トラスティーズ・オブ・ダートマス・カレッジ | VISTA modulators for cancer diagnosis and treatment |
Non-Patent Citations (3)
Title |
---|
Biologics:Targets and Therapy vol.6 pp.379-383(2012.11.01. 공개) * |
Cancer Research, vol.42 no.2 pp.537-547(2011.11.23. 온라인 공개)* * |
Scientific Reports volume 6, Article number: 24912(2016.04.25. 공개)* * |
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