KR20200139350A - Pharmaceutical composition for preventing, treating and inhibiting metastasis of breast cancer comprising fermented soybean extract suppressing PLAU and ERBB2 expressions - Google Patents
Pharmaceutical composition for preventing, treating and inhibiting metastasis of breast cancer comprising fermented soybean extract suppressing PLAU and ERBB2 expressions Download PDFInfo
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- KR20200139350A KR20200139350A KR1020190065726A KR20190065726A KR20200139350A KR 20200139350 A KR20200139350 A KR 20200139350A KR 1020190065726 A KR1020190065726 A KR 1020190065726A KR 20190065726 A KR20190065726 A KR 20190065726A KR 20200139350 A KR20200139350 A KR 20200139350A
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- breast cancer
- soybean
- protein
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A61P35/04—Antineoplastic agents specific for metastasis
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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Abstract
Description
본 발명은 PLAU 단백질 및 ERBB2 단백질의 발현을 억제하는 대두 발효 추출물을 유효성분으로 포함하는 유방암의 예방, 치료 또는 전이억제용 약학적 조성물에 관한 것으로, 더욱 상세하게는 PLAU 단백질 또는 ERBB2 단백질의 발현 또는 활성을 억제하는 대두 발효 추출물을 유효성분으로 포함하는 유방암의 예방, 치료 또는 전이억제용 약학적 조성물, 유방암의 예방, 개선 또는 전이억제용 식품 조성물, 및 유방암의 치료 또는 전이 억제 방법에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer comprising a fermented soybean extract that inhibits the expression of PLAU protein and ERBB2 protein as an active ingredient, and more particularly, to the expression of PLAU protein or ERBB2 protein or It relates to a pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer comprising a soybean ferment extract that inhibits activity as an active ingredient, a food composition for preventing, improving or inhibiting metastasis of breast cancer, and a method of treating or inhibiting metastasis of breast cancer.
유방암(breast cancer)은 유방에 발생하는 모든 악성 종양을 통틀어 말하는 것으로, 유방에 비정상적인 세포조직이 계속 자라거나 다른 장기로 퍼지는 치명적인 질병이다. 한국 여성들에게 있어서 유방암 발병률은 갑상선 암에 이어서 두 번째이며, 유방암 발병률은 20대 및 30대에서 증가하다가 40대에서 최고에 이른다. Breast cancer refers to all malignant tumors in the breast. It is a fatal disease in which abnormal tissues in the breast continue to grow or spread to other organs. In Korean women, the incidence of breast cancer is second only to thyroid cancer, and the incidence of breast cancer increases in their 20s and 30s and reaches the highest in their 40s.
유방암의 치료는 조기 진단시 외과적 절제술로 치료가 가능하나 많은 환자에서 폐, 뼈, 간 등 원격적인 전이 형태로 재발된다. 암 세포의 전이(metastasis)는 암 치료를 어렵게 하는데, 이 때 세포를 둘러싸고 있는 조직으로 침투해 들어가는 세포 침윤(invasion) 과정이 필수적이며 이는 악성 암세포의 특징 중 하나이다(Aznavoorian et al., Cancer 71,1368-1383, 1993). 암세포의 침윤성에는 세포외 기질(extracellular matrix, ECM)과 기저막(basement membrane)을 분해하는 단백질 분해과정과 분해된 매트릭스(matrix)를 통하여 이동하는 세포 이동성(migration)이 관여한다.The treatment of breast cancer can be treated with surgical resection at early diagnosis, but many patients recur as distant metastases such as lungs, bones, and liver. Metastasis of cancer cells makes cancer treatment difficult. In this case, a cell invasion process that penetrates into the surrounding tissues is essential, which is one of the characteristics of malignant cancer cells (Aznavoorian et al., Cancer 71, 1368-1383, 1993). The invasiveness of cancer cells involves proteolysis, which degrades the extracellular matrix (ECM) and the basement membrane, and cell migration, which moves through the degraded matrix.
이러한 유방암의 예방 및 치료용 약학적 조성물에 대한 종래 기술로서, 등록특허 제0909998호는 아라자임을 유효성분으로 하는 유방암 예방 및 치료용 약학적 조성물에 대하여 개시하고 있다. 그러나, 이러한 종래 기술은 상기 조성물이 사전에 어떤 단백질의 발현에 영향을 미치는지 예측하기 어렵다는 점에서 유방암 치료제 개발에 어려움이 있었다.As a prior art for such a pharmaceutical composition for preventing and treating breast cancer, Korean Patent No. 0909998 discloses a pharmaceutical composition for preventing and treating breast cancer using arazyme as an active ingredient. However, this prior art has difficulty in developing a treatment for breast cancer in that it is difficult to predict which protein the composition affects in advance.
이에 본 발명자들은 유방암세포의 마이크로어레이 데이터(microarray data)와 잘 알려진 유방암 전이 마커를 합쳐서 새로운 연결망을 제조하고 이러한 연결망 분석을 통해 유방암세포를 청국장 추출물로 처리하고 PLAU와 ERBB2 단백질의 발현정도를 측정한 결과 청국장 추출물이 PLAU와 ERBB2 단백질의 발현을 억제한다는 것을 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors prepared a new network by combining microarray data of breast cancer cells with well-known breast cancer metastasis markers, and treated breast cancer cells with Cheongkukjang extract through this network analysis, and measured the expression level of PLAU and ERBB2 proteins. Results The present invention was completed by confirming that the extract of Cheonggukjang inhibits the expression of PLAU and ERBB2 proteins.
따라서 본 발명의 목적은 PLAU(plasminogen activator, urokinase) 단백질 또는 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제하는 대두 발효 추출물을 유효성분으로 포함하는 유방암의 예방, 치료 또는 전이억제용 약학적 조성물, 유방암의 예방, 개선 또는 전이억제용 식품 조성물 및 유방암의 치료 또는 전이 억제 방법을 제공하는데 있다.Accordingly, an object of the present invention is a pharmaceutical for preventing, treating or inhibiting metastasis of breast cancer comprising a soybean ferment extract that inhibits the expression or activity of PLAU (plasminogen activator, urokinase) protein or ERBB2 (epidermal growth factor receptor 2) protein as an active ingredient. It is to provide a composition, a food composition for preventing, improving or inhibiting metastasis of breast cancer, and a method of treating or inhibiting metastasis of breast cancer.
본 발명의 다른 목적은 PLAU(plasminogen activator, urokinase) 단백질의 발현 또는 활성 억제제를 유효성분으로 포함하는 유방암의 예방, 치료 또는 전이억제용 약학적 조성물을 제공하는데 있다.Another object of the present invention is to provide a pharmaceutical composition for preventing, treating, or inhibiting metastasis of breast cancer comprising an inhibitor of the expression or activity of a PLAU (plasminogen activator, urokinase) protein as an active ingredient.
상술한 목적을 달성하기 위한 본 발명의 바람직한 일 실시예에 따른 유방암의 예방, 치료 또는 전이억제용 약학적 조성물은 PLAU(plasminogen activator, urokinase) 단백질 및 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제하는 대두 발효 추출물을 유효성분으로 포함한다.The pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer according to a preferred embodiment of the present invention to achieve the above object is PLAU (plasminogen activator, urokinase) protein and ERBB2 (epidermal growth factor receptor 2) protein expression or It contains a soybean ferment extract that inhibits activity as an active ingredient.
본 발명의 바람직한 다른 실시예에 따른 유방암의 예방, 치료 또는 전이억제용 약학적 조성물은 PLAU(plasminogen activator, urokinase) 단백질의 발현 또는 활성 억제제를 유효성분으로 포함한다.The pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer according to another preferred embodiment of the present invention includes an inhibitor of the expression or activity of a plasminogen activator (PLA) protein as an active ingredient.
또한, 본 발명에 따른 유방암의 예방, 치료 또는 전이억제용 약학적 조성물에 있어서, 상기 대두 발효 추출물은 Bacillus licheniformis 균주로 대두를 발효시킨 추출물인 것을 특징으로 한다.In addition, in the pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer according to the present invention, the fermented soybean extract is an extract obtained by fermenting soybeans with Bacillus licheniformis strain.
또한, 본 발명에 따른 유방암의 예방, 치료 또는 전이억제용 약학적 조성물에 있어서, 상기 대두 발효 추출물은 Bacillus licheniformis 균주로 대두를 발효시킨 대두 발효물을 에탄올로 추출하여 제조된 청국장 추출물이고, 상기 대두 발효 추출물은 Ala-Phe-Pro-Gly, Gly-Val-Ala-Trp-Trp-Met-Tyr, Lys-Pro 및 Gln-Lys 으로 이루어진 군 중에서 1종 이상 선택되는 펩타이드를 포함하는 것을 특징으로 한다.In addition, in the pharmaceutical composition for preventing, treating, or inhibiting metastasis of breast cancer according to the present invention, the soybean fermentation extract is a soybean fermentation product obtained by fermenting soybeans with Bacillus licheniformis strain, and is an extract of cheonggukjang prepared by extracting with ethanol The fermentation extract is characterized by containing a peptide selected from one or more of the group consisting of Ala-Phe-Pro-Gly, Gly-Val-Ala-Trp-Trp-Met-Tyr, Lys-Pro, and Gln-Lys.
또한, 본 발명에 따른 유방암의 예방, 치료 또는 전이억제용 약학적 조성물에 있어서, 상기 조성물이 유방암 세포의 성장 억제 및 전이(metastasis) 억제 효과를 갖는 것을 특징으로 한다.In addition, in the pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer according to the present invention, the composition is characterized in that it has an effect of inhibiting the growth of breast cancer cells and inhibiting metastasis (metastasis).
본 발명의 바람직한 다른 실시예에 따른 유방암의 예방, 개선 또는 전이억제용 식품 조성물은 PLAU(plasminogen activator, urokinase) 단백질 및 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제하는 대두 발효 추출물을 유효성분으로 포함한다.The food composition for preventing, improving or inhibiting metastasis of breast cancer according to another preferred embodiment of the present invention comprises a fermented soybean extract that inhibits the expression or activity of a plasminogen activator, urokinase (PLA) protein and an epidermal growth factor receptor 2 (ERBB2) protein. Included as an active ingredient.
또한, 본 발명에 따른 유방암의 예방, 개선 또는 전이억제용 식품 조성물에 있어서, 상기 대두 발효 추출물은 Bacillus licheniformis B1 균주로 대두를 발효시킨 추출물인 것을 특징으로 한다.In addition, in the food composition for preventing, improving or inhibiting metastasis of breast cancer according to the present invention, the fermented soybean extract is an extract obtained by fermenting soybeans with Bacillus licheniformis B1 strain.
본 발명의 바람직한 다른 실시예에 따른 유방암의 치료 또는 전이 억제 방법은 PLAU(plasminogen activator, urokinase) 단백질 및 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제하는 대두 발효 추출물을 인간을 제외한 개체에 투여하는 단계를 포함한다.A method for treating or inhibiting metastasis of breast cancer according to another preferred embodiment of the present invention includes a soybean fermented extract that inhibits the expression or activity of a PLAU (plasminogen activator, urokinase) protein and ERBB2 (epidermal growth factor receptor 2) protein. And administering to.
또한, 본 발명에 따른 유방암의 치료 또는 전이 억제 방법에 있어서, 상기 대두 발효 추출물은 Bacillus licheniformis B1 균주로 대두를 발효시킨 대두 발효물을 에탄올로 추출하여 제조된 청국장 추출물인 것을 특징으로 한다.In addition, in the method for treating or inhibiting metastasis of breast cancer according to the present invention, the fermented soybean extract is a cheonggukjang extract prepared by extracting a soybean fermented soybean fermented with Bacillus licheniformis B1 strain with ethanol.
본 발명에 따르면, 본 발명의 대두 발효 추출물을 유효성분으로 포함하는 유방암의 예방, 치료 또는 전이억제용 약학적 조성물, 유방암의 예방, 개선 또는 전이억제용 식품 조성물 및 유방암의 치료 또는 전이 억제 방법은 PLAU(plasminogen activator, urokinase) 단백질 또는 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제할 수 있다.According to the present invention, a pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer comprising a fermented soybean extract of the present invention as an active ingredient, a food composition for preventing, improving or inhibiting metastasis of breast cancer, and a method of treating or inhibiting metastasis of breast cancer It can inhibit the expression or activity of a PLAU (plasminogen activator, urokinase) protein or ERBB2 (epidermal growth factor receptor 2) protein.
또한, 본 발명의 유방암의 예방, 치료 또는 전이억제용 약학적 조성물은 PLAU(plasminogen activator, urokinase) 단백질의 발현 또는 활성을 억제할 수 있다.In addition, the pharmaceutical composition for preventing, treating, or inhibiting metastasis of breast cancer of the present invention may inhibit the expression or activity of a PLAU (plasminogen activator, urokinase) protein.
도 1은 본 발명의 일 실시예에 따른 연결망(네트워크) 분석도이다. 암전이 마커와 관련된 단백질은 붉은색으로 표시되고, 발효된 대두의 마이크로어레이 데이터 기반 연결망에서 유래한 단백질은 청색으로 표시되었다. 녹색 단백질은 암전이 마커 단백질과 마이크로어레이 단백질을를 연결한다. 노란색은 암전이 및 마이크로 어레이데이터 기반 연결망(네트워크) 단백질임을 표시한다.
도 2는 본 발명의 일 실시예에 따른 PLAU 및 ERBB2의 발현을 나타내는 그래프이다. (A)는 PLAU 발현 결과이다. MCF7 세포에서 PLAU mRNA의 증폭을 위한 실시간 PCR이 수행되었다. β- 액틴 mRNA는 내부 컨트롤로서 증폭되었다. 0.1 mg/ml 대두 발효 추출물(P) 및 무첨가(C)로 처리된 MCF7 세포에서 PLAU 발현을 실시간 PCR 수행 후 비교되었다. C의 값은 1이고 P의 값은 0.46이다. (B)는 ERBB2 발현 결과이다. MCF7 세포에서 ERBB2 mRNA의 증폭을 위한 실시간 PCR이 수행되었다. 0.1 mg/ml 대두 발효 추출물(P) 및 무첨가(C)로 처리된 MCF7 세포에서 ERBB2 발현을 실시간 PCR 수행 후 비교되었다. C의 값은 1이고 P의 값은 0.30이다.
도 3은 본 발명의 일 실시예에 따른 NO 분석 결과이다. MCF7 세포를 0.5 mg/ml 대두 발효 추출물로 1일(0.5) 처리하였다. 세포를 NO 형광 분석 프로브에 넣고 1.5 시간 동안 저장하였다. FITC 필터가 장착된 형광 현미경(DMi8, Leica)을 이용하여 세포 이미지 (A), (B)를 얻었다. Image J 프로그램을 사용하여 세포의 강도를 측정하였다(C).1 is a diagram illustrating a connection network (network) according to an embodiment of the present invention. Proteins related to cancer metastasis markers are indicated in red, and proteins derived from microarray data-based networks of fermented soybeans are indicated in blue. The green protein connects the cancer metastasis marker protein and the microarray protein. Yellow indicates cancer metastasis and microarray data-based network (network) protein.
2 is a graph showing the expression of PLAU and ERBB2 according to an embodiment of the present invention. (A) is the PLAU expression result. Real-time PCR for amplification of PLAU mRNA was performed in MCF7 cells. β-actin mRNA was amplified as an internal control. PLAU expression in MCF7 cells treated with 0.1 mg/ml soybean ferment extract (P) and no addition (C) was compared after real-time PCR. The value of C is 1 and the value of P is 0.46. (B) is the result of ERBB2 expression. Real-time PCR for amplification of ERBB2 mRNA was performed in MCF7 cells. ERBB2 expression in MCF7 cells treated with 0.1 mg/ml soybean fermentation extract (P) and no addition (C) was compared after real-time PCR. The value of C is 1 and the value of P is 0.30.
3 is a NO analysis result according to an embodiment of the present invention. MCF7 cells were treated with 0.5 mg/ml soybean fermented extract for 1 day (0.5). The cells were placed in the NO fluorescence assay probe and stored for 1.5 hours. Cell images (A) and (B) were obtained using a fluorescence microscope equipped with a FITC filter (DMi8, Leica). The strength of the cells was measured using the Image J program (C).
본 발명은 다양한 변환을 가할 수 있고 여러 가지 실시 예를 가질 수 있는 바, 특정 실시 예들을 상세한 설명에서 상세하게 설명하고자 한다. 그러나, 이는 본 발명을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 본 발명의 사상 및 기술 범위에 포함되는 모든 변환, 균등물 내지 대체물을 포함하는 것으로 이해되어야 한다. 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.Since the present invention can apply various transformations and have various embodiments, specific embodiments will be described in detail in the detailed description. However, this is not intended to limit the present invention to a specific embodiment, it is to be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, when it is determined that a detailed description of a related known technology may obscure the subject matter of the present invention, a detailed description thereof will be omitted.
이하, 도면들을 참조하여 본 발명의 실시예에 대해 상세히 설명하기로 한다. 본 발명은 본 발명의 정신 및 필수적 특징을 벗어나지 않는 범위에서 다른 특정한 형태로 구체화될 수 있음은 당업자에게 자명하다.Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the drawings. It is obvious to those skilled in the art that the present invention can be embodied in other specific forms without departing from the spirit and essential features of the present invention.
본 발명의 바람직한 일 실시예에 따른 유방암의 예방, 치료 또는 전이억제용 약학적 조성물은 PLAU(plasminogen activator, urokinase) 단백질 및 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제하는 대두 발효 추출물을 유효성분으로 포함한다.The pharmaceutical composition for preventing, treating, or inhibiting metastasis of breast cancer according to a preferred embodiment of the present invention is a soybean fermented extract that inhibits the expression or activity of PLAU (plasminogen activator, urokinase) protein and ERBB2 (epidermal growth factor receptor 2) protein. It contains as an active ingredient.
상기 대두 발효 추출물은 Bacillus licheniformis 균주로 대두를 발효시킨 대두 발효물을 에탄올로 추출하여 제조된 청국장 추출물인 것을 특징으로 한다. The soybean fermentation extract is characterized in that the soybean fermentation product obtained by fermenting soybeans with Bacillus licheniformis strain is extracted with ethanol, and is a cheonggukjang extract.
상기 Bacillus licheniformis 균주는 Bacillus licheniformis B1 균주인 것이 바람직하고, 본 발명의 실시예에서 사용한 상기 바실러스 리케니포미스(Bacillus licheniformis) B1은 본 발명자가 대한민국 특허출원 제2000-18724호로 특허출원하여 대한민국 특허등록 제0368183호로 특허받은 것에 따른 KCTC 0755BP 균주이다. The Bacillus licheniformis strain is preferably a Bacillus licheniformis B1 strain, and the Bacillus licheniformis B1 used in the embodiment of the present invention was registered as a Korean patent by the inventors by applying for a patent in Korean Patent Application No. 2000-18724. It is a KCTC 0755BP strain according to the patented No. 0368183.
바람직하게는, 상기 대두 발효 추출물은 Ala-Phe-Pro-Gly, Gly-Val-Ala-Trp-Trp-Met-Tyr, Lys-Pro 및 Gln-Lys 으로 이루어진 군 중에서 1종 이상 선택되는 펩티드를 포함하는 것을 특징으로 한다.Preferably, the soybean fermentation extract contains a peptide selected from the group consisting of Ala-Phe-Pro-Gly, Gly-Val-Ala-Trp-Trp-Met-Tyr, Lys-Pro, and Gln-Lys. Characterized in that.
본 발명의 다른 실시예에 따른 유방암의 예방, 치료 또는 전이억제용 약학적 조성물은 PLAU(plasminogen activator, urokinase) 단백질의 발현 또는 활성 억제제를 유효성분으로 포함한다. 상기 PLAU(plasminogen activator, urokinase) 단백질의 발현 또는 활성 억제제는 전술한 대두 발효 추출물이다.The pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer according to another embodiment of the present invention includes an inhibitor of the expression or activity of a plasminogen activator (PLA) protein as an active ingredient. The PLAU (plasminogen activator, urokinase) protein expression or activity inhibitor is the above-described soybean fermented extract.
본 발명에서 용어, "유방암"은 유방에 생긴 암세포로 이루어진 종괴를 의미하며, 일반적으로는 유방의 유관과 소엽에서 발생한 암을 의미한다. 예컨대, 유방암은 생검(biopsy)에 의해 악성 병리상태로 분류되는 상태로, 유방암 진단의 임상적인 기술은 의학 분야에 잘 알려져 있다. 당업자라면 유방암이, 예컨대 악성 종양 및 육종을 포함한, 유방 조직의 모든 악성을 나타냄을 이해할 것이다. 예시적으로, 유방암은 유방내암(ductal carcinomain situ, DCIS), 상피내 소엽성 암종(lobular carcinoma in situ, LCIS), 점액성 유방암(mucinous carcinoma), 침윤성 관상피암(infiltrating ductal carcinoma, IDC), 침윤성 소엽내암(infiltrating lobular carcinoma,ILC) 등을 포함한다. In the present invention, the term "breast cancer" means a mass made of cancer cells in the breast, and generally means cancer arising from the ducts and lobules of the breast. For example, breast cancer is a condition classified as a malignant pathology by biopsy, and clinical techniques for diagnosing breast cancer are well known in the medical field. Those skilled in the art will understand that breast cancer represents all malignancy of breast tissue, including, for example, malignant tumors and sarcomas. For example, breast cancer is ductal carcinomain situ (DCIS), lobular carcinoma in situ (LCS), mucinous carcinoma, infiltrating ductal carcinoma (IDC), invasive lobular carcinoma. And infiltrating lobular carcinoma (ILC).
본 발명에서 용어, "PLAU(plasminogen activator, urokinase)"는 플라스미노겐이 분해되어 생성된 플라스민의 활성화를 촉매하는 유로키나제(urokinase, uPA)를 말한다. In the present invention, the term "PLAU (plasminogen activator, urokinase)" refers to urokinase (uPA) that catalyzes the activation of plasmin generated by decomposition of plasminogen.
본 발명에서 용어, "ERBB2(epidermal growth factor receptor 2)"는 유방암 세포의 증식과 생존에 관계하는 중요한 신호전달 체계 중의 하나인 상피세포 성장인자수용체 (epidermal growth factor receptor; EGFR) 패밀리로서, HER2라고도 한다. EGFR 패밀리의 티로신 인산화효소 수용체(receptor tyrosine kinases)는 erb1, erb2/HER2, erb3, erb4의 4개로 되어 있으며 세포 증식(proliferation)과 생존(survival) 외에도 세포의 부착(adhesion), 이동(migration) 및 분화(differentiation)를 조절하는데 관여하는 것으로 알려져 있다. 4개의 erb family 중 erb2/HER2가 결합하는 리간드는 없지만 유방암에서 가장 강력한 암유전자(oncoprotein)로 알려져 있다. HER2가 정상적인 수준인 경우에는 정상적인 유선조직의 성장과 발달에 관여하지만, 비정상적으로 HER2가 과발현하거나 증폭되면 정상세포 조절이 붕괴되어 유선조직에서는 공격적인 암세포가 형성되게 된다. In the present invention, the term "ERBB2 (epidermal growth factor receptor 2)" is an epidermal growth factor receptor (EGFR) family, which is one of the important signaling systems related to the proliferation and survival of breast cancer cells, and is also called HER2. do. The tyrosine receptor tyrosine kinases of the EGFR family are composed of erb1, erb2/HER2, erb3, and erb4. In addition to cell proliferation and survival, adhesion, migration, and It is known to be involved in regulating differentiation. Of the four erb families, there is no ligand to which erb2/HER2 binds, but it is known as the most powerful oncoprotein in breast cancer. When HER2 is at a normal level, it is involved in the growth and development of normal mammary tissue. However, when HER2 is abnormally overexpressed or amplified, normal cell regulation is disrupted and aggressive cancer cells are formed in the mammary tissue.
본 발명에서 용어 "전이 (metastasis)"는 악성 종양이 발병한 장기에서 떨어진 다른 조직으로 전파한 상태를 말한다. 하나의 장기에서 시작한 악성 종양이 진행함에 따라 처음 발생한 원발 부위인 장기로부터 다른 조직으로 퍼져 나가는데, 이렇게 원발 부위로부터 다른 조직으로 퍼져 나가는 것을 전이라 할 수 있다. 전이는 악성 종양의 진행에 수반되는 현상이라고 할 수 있는데, 악성 종양 세포가 증식하고 암이 진행함에 따라 새로운 유전 형질을 획득하면서 전이가 일어날 수 있다. 새로운 유전 형질을 획득한 종양 세포가 혈관과 림프선으로 침입하고 혈액과 림프를 따라 순환하다가 다른 조직에 정착, 증식하게 되면 전이가 일어날 수 있다. 전이가 발생하는 조직에 따라, 간암, 신장암, 폐암, 위암, 대장암, 직장암, 췌장암 등 각종 암질환이 유발될 수 있다. 본 발명의 조성물은 전이를 억제하여 암이 퍼지는 것을 예방 및 치료할 수 있다.In the present invention, the term "metastasis" refers to a condition in which a malignant tumor has spread to other tissues away from the diseased organ. As a malignant tumor that started in one organ progresses, it spreads from the first primary site, the organ, to other tissues, and this spreading from the primary site to other tissues can be called before. Metastasis can be said to be a phenomenon accompanying the progression of a malignant tumor. As the malignant tumor cells proliferate and the cancer progresses, metastasis can occur while acquiring new genetic traits. Metastasis can occur when tumor cells that have acquired a new genetic trait invade blood vessels and lymph glands, circulate along blood and lymph, and settle and proliferate in other tissues. Depending on the tissue where metastasis occurs, various cancer diseases such as liver cancer, kidney cancer, lung cancer, gastric cancer, colon cancer, rectal cancer, and pancreatic cancer can be caused. The composition of the present invention can prevent and treat cancer spreading by inhibiting metastasis.
본 발명에서 용어, "억제"는 본 발명에 따른 조성물의 투여로 PLAU(plasminogen activator, urokinase) 단백질 또는 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제시키고, 유방암 세포의 성장 억제 및 상기 유방암의 전이를 억제시키는 모든 행위를 말한다.In the present invention, the term "inhibition" refers to inhibiting the expression or activity of a PLAU (plasminogen activator, urokinase) protein or ERBB2 (epidermal growth factor receptor 2) protein by administration of the composition according to the present invention, and inhibiting the growth of breast cancer cells and the above Any action that inhibits the metastasis of breast cancer.
본 발명의 구체적인 일 실시예에서는 유방암세포를 청국장 추출물로 처리하고 PLAU와 ERBB2 발현정도를 측정한 결과, 청국장 추출물이 PLAU와 ERBB2 발현을 상당히 억제한다는 것을 확인하였다(도 2). In a specific embodiment of the present invention, as a result of treating breast cancer cells with Cheonggukjang extract and measuring the expression level of PLAU and ERBB2, it was confirmed that the Cheonggukjang extract significantly inhibited the expression of PLAU and ERBB2 (FIG. 2).
즉, 본 발명의 실시예에 따르면, 발효대두 청국장에는 대두단백질이 발효에 의해 분해 형성된 다양한 펩타이드류가 들어 있고, 이러한 청국장 추출물이 처리된 유방암세포의 microarray data와 잘 알려진 유방암 전이 마커를 합쳐서 새로운 연결망이 제조되었으며 이를 이용해 전이 마커와 발현 차이가 있는 단백질 사이의 상호작용을 체크하였다. 이러한 연결망 분석을 통해 PLAU (plasminogen activator, urokinase, uPA)와 ERBB2 (epidermal growth factor receptor 2)를 실제 전이 가능성을 보여주는 유전자로 선택하였고, MCF7 암세포를 청국장추출물로 처리하고 PLAU와 ERBB2 발현정도를 측정한 결과, 청국장 추출물이 PLAU와 ERBB2 발현을 억제하였다. That is, according to an embodiment of the present invention, fermented soybean cheonggukjang contains various peptides formed by decomposition of soybean protein by fermentation, and a new network by combining microarray data of breast cancer cells treated with such cheonggukjang extract with well-known breast cancer metastasis markers. Was prepared, and the interaction between the metastasis marker and the protein having a difference in expression was checked using this. Through this network analysis, PLAU (plasminogen activator, urokinase, uPA) and ERBB2 (epidermal growth factor receptor 2) were selected as genes showing the actual metastasis potential, and MCF7 cancer cells were treated with Cheongkukjang extract and the expression levels of PLAU and ERBB2 were measured. As a result, Cheonggukjang extract inhibited PLAU and ERBB2 expression.
본 발명의 다른 구체적인 일 실시예에서는 청국장 추출물을 처리한 유방암세포에서 염증 마커인 NO의 생산이 감소하였음을 확인하였다(도 3).In another specific embodiment of the present invention, it was confirmed that the production of NO, an inflammatory marker, was reduced in breast cancer cells treated with the extract of Cheonggukjang (FIG. 3).
이에, 본 발명자들은 상기 결과를 통해 청국장 추출물이 유방암세포의 PLAU와 ERBB2의 발현을 상당히 억제한다는 것을 확인하였다.Thus, the present inventors confirmed through the above results that the extract of Cheonggukjang significantly inhibited the expression of PLAU and ERBB2 in breast cancer cells.
본 발명의 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. 약학적으로 허용 가능한 담체를 포함하는 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구 투여를 위한 고형제제에는 정제환제, 산제, 과립제, 캡슐제 등이 포함될 수 있으며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용될 수 있다. 경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함될 수 있다. 비수성용제, 현탁용제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The pharmaceutical composition of the present invention may further include an appropriate carrier, excipient, or diluent commonly used in the preparation of pharmaceutical compositions. Compositions containing a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. In the case of formulation, it can be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration may include tablet pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient, such as starch, calcium carbonate, sucrose, or lactose in one or more compounds. (lactose), gelatin, etc. can be mixed to prepare. Further, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, syrups, etc.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, and preservatives may be included. have. Preparations for parenteral administration may include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.
또한, 본 발명의 약학 조성물은 이에 제한되지는 않으나, 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있다.In addition, the pharmaceutical composition of the present invention is not limited thereto, but tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations And it may have any one formulation selected from the group consisting of suppositories.
본 발명에서 용어, "치료"는 치료하고자 하는 개개인 또는 세포의 천연 과정을 변경시키기 위해 임상적으로 개입하는 것을 지칭하고, 이는 임상 병리 상태가 진행되는 동안 또는 이를 예방하기 위해 수행할 수 있다. 목적하는 치료 효과에는 질병의 발생 또는 재발을 예방하고, 증상을 완화시키며, 질병에 따른 모든 직접 또는 간접적인 병리학적 결과를 저하시키며, 전이를 예방하고, 질병 진행 속도를 감소시키며, 질병 상태를 경감 또는 일시적 완화시키며, 차도시키거나 예후를 개선시키는 것이 포함된다. 또한, "예방"은 본 발명에 따른 조성물의 투여로 상기 암의 발병을 억제 또는 지연시키는 모든 행위를 말한다.In the present invention, the term "treatment" refers to clinical intervention in order to alter the natural process of an individual or cell to be treated, and this may be performed while a clinical pathology is progressing or to prevent it. The desired therapeutic effect includes preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing all direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, and alleviating the disease state. Or temporary alleviation, remission, or improving prognosis. In addition, "prevention" refers to any action of inhibiting or delaying the onset of the cancer by administration of the composition according to the present invention.
본 발명의 대두 발효 추출물을 유효성분으로 포함하는 조성물은 PLAU(plasminogen activator, urokinase) 단백질 및 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제하는 효과가 있으므로 유방암의 예방, 치료 또는 전이억제용 조성물로 우수한 효과가 있다.The composition comprising the fermented soybean extract of the present invention as an active ingredient has the effect of inhibiting the expression or activity of the PLAU (plasminogen activator, urokinase) protein and the ERBB2 (epidermal growth factor receptor 2) protein, thus preventing, treating or inhibiting metastasis of breast cancer. It has an excellent effect as a solvent composition.
또한, 본 발명의 조성물은 PLAU(plasminogen activator, urokinase) 단백질의 발현 또는 활성 억제제를 유효성분으로 포함하여 유방암의 예방, 치료 또는 전이억제용 조성물로 우수한 효과가 있다.In addition, the composition of the present invention has an excellent effect as a composition for preventing, treating, or inhibiting metastasis of breast cancer, including an inhibitor of the expression or activity of a PLAU (plasminogen activator, urokinase) protein as an active ingredient.
본 발명의 다른 실시예에 따른 유방암의 예방, 개선 또는 전이억제용 식품 조성물은 PLAU(plasminogen activator, urokinase) 단백질 및 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제하는 대두 발효 추출물을 유효성분으로 포함한다.The food composition for preventing, improving, or inhibiting metastasis of breast cancer according to another embodiment of the present invention is effective in the soybean fermented extract that inhibits the expression or activity of PLAU (plasminogen activator, urokinase) protein and ERBB2 (epidermal growth factor receptor 2) protein. Included as an ingredient.
상기 대두 발효 추출물은 전술한 바와 같이 Bacillus licheniformis 균주로 대두를 발효시킨 대두 발효물을 에탄올로 추출하여 제조된 청국장 추출물인 것을 특징으로 한다.The soybean fermentation extract is characterized in that it is a cheonggukjang extract prepared by extracting a soybean fermented product obtained by fermenting soybeans with Bacillus licheniformis strain as described above with ethanol.
본 발명에서 용어, "개선"은 대두 발효 추출물을 유효성분으로 포함하는 조성물을 이용하여 PLAU(plasminogen activator, urokinase) 단백질 및 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제하여 상기 질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 되는 모든 행위를 말한다.In the present invention, the term "improvement" refers to the expression or activity of PLAU (plasminogen activator, urokinase) protein and ERBB2 (epidermal growth factor receptor 2) protein by using a composition containing fermented soybean extract as an active ingredient. Any action that improves or benefits the symptoms of suspected and affected individuals.
상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 천연 과일쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 추출물을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다.The food composition includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and thickeners (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids , A protective colloid thickener, a pH adjuster, a stabilizer, a preservative, a glycerin, an alcohol, a carbonation agent used in carbonated beverages, and the like. In addition, it may contain extracts for the manufacture of natural fruit juices and fruit juice beverages and vegetable beverages. These components may be used independently or in combination.
또한, 상기 식품 조성물은 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 껌류, 아이스크림류, 스프, 음료수, 차, 기능수, 드링크제, 알코올 음료 및 비타민 복합제 중 어느 하나의 형태일 수 있다.In addition, the food composition is any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcoholic beverage and vitamin complex Can be
본 발명의 다른 실시예는 PLAU(plasminogen activator, urokinase) 단백질 및 ERBB2(epidermal growth factor receptor 2) 단백질의 발현 또는 활성을 억제하는 대두 발효 추출물을 인간을 제외한 개체에 투여하는 단계를 포함하는 유방암의 치료 또는 전이 억제 방법이다.Another embodiment of the present invention is a treatment of breast cancer comprising administering a soybean ferment extract that inhibits the expression or activity of PLAU (plasminogen activator, urokinase) protein and ERBB2 (epidermal growth factor receptor 2) protein to individuals other than humans. Or metastasis inhibition method.
본 발명에서 용어, "개체"는 본 발명의 암 질환을 보유하거나 또는 발병한, 인간을 포함한 모든 동물을 의미하며, 인간을 제외한 개체일 수 있다. 본 발명의 약학 조성물을 개체에 투여함으로써, 간암을 비롯한 암의 전이를 억제할 수 있다.In the present invention, the term "individual" means all animals, including humans, possessing or developing the cancer disease of the present invention, and may be an individual other than humans. By administering the pharmaceutical composition of the present invention to an individual, metastasis of cancer including liver cancer can be suppressed.
상기 본 발명의 약학 조성물은 약학적으로 유효한 양으로 투여한다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
본 발명에서 용어, "투여"는 어떠한 적절한 방법으로 대상에게 본 발명의 약학 조성물을 도입하는 것을 말하며, 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다.In the present invention, the term "administration" refers to introducing the pharmaceutical composition of the present invention to a subject by any suitable method, and the route of administration may be administered through various routes, either oral or parenteral, as long as it can reach the target tissue.
상기 약학 조성물은 목적 또는 필요에 따라 당업계에서 사용되는 통상적인 방법, 투여 경로, 투여량에 따라 적절하게 개체에 투여될 수 있다. 투여 경로의 예로는 경구, 비경구, 피하, 복강 내, 폐 내, 및 비강 내로 투여될 수 있으며, 비경구 주입에는 근육 내, 정맥 내, 동맥 내, 복강 내 또는 피하투여가 포함된다. 또한 당업계에 공지된 방법에 따라 적절한 투여량 및 투여 횟수가 선택될 수 있으며, 실제로 투여되는 본 발명의 약학 조성물의 양 및 투여 횟수는 치료하고자 하는 증상의 종류, 투여 경로, 성별, 건강 상태, 식이, 개체의 연령 및 체중, 및 질환의 중증도와 같은 다양한 인자에 의해 적절하게 결정될 수 있다.The pharmaceutical composition may be appropriately administered to a subject according to a conventional method, route of administration, and dosage used in the art, depending on the purpose or need. Examples of the route of administration may be oral, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal administration, and parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. In addition, an appropriate dosage and number of administrations may be selected according to methods known in the art, and the amount and number of administrations of the pharmaceutical composition of the present invention to be actually administered are the type of symptom to be treated, route of administration, sex, health condition, It can be appropriately determined by various factors such as diet, age and weight of the individual, and the severity of the disease.
본 발명에서의 용어 "약학적으로 유효한 양"은 의학적 용도에 적용 가능한 합리적인 수혜/위험 비율로 혈관 투과성 증가를 억제 또는 완화하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The term "pharmaceutically effective amount" in the present invention means an amount sufficient to inhibit or alleviate the increase in vascular permeability at a reasonable benefit/risk ratio applicable to medical use, and the effective dose level is the type and severity of the subject, age, Sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and can be easily determined by a person skilled in the art.
이하, 실시예를 통하여 본 발명을 더욱 상세하게 설명하고자 하나, 하기의 실시예는 단지 설명의 목적을 위한 것이며, 본 발명의 범위를 한정하고자 하는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
실시예 1: 유방암 세포주 및 대두 발효 추출물 처리Example 1: Breast cancer cell line and soybean fermentation extract treatment
대두 발효 추출물에 대한 마이크로어레이 분석 결과에 기반하여 상이하게 발현된 유전자들 및 공지된 유방암 전이 마커들인 ERBB2, MMP1, MMP9, CD9, ADAM9 및 BCL2을 모두 포함한 이들 간의 상호 작용을 확인하기 위하여 새로운 연결망(네트워크) 분석을 진행하였다. Based on the microarray analysis results of the soybean fermented extract, a new network was used to confirm the interactions between differently expressed genes and known breast cancer metastasis markers, including all of ERBB2, MMP1, MMP9, CD9, ADAM9 and BCL2. Network) analysis was performed.
MCF7 세포를 DMEM 배지(Dulbecco’s Modification of Eagle’s medium, Cornig)에 10% 소 태아 혈청(Fetal Bovine Serum), 1% 항생제-항균제(Caisson), 및 대두 발효 추출물을 첨가하여 37°C, 5% CO2 하에서 배양하였다. 대두는 Bacillus licheniformis B1으로 발효시키고, 발효된 대두를 에탄올로 추출하여 대두 발효 추출물을 제조하였다. 대두를 발효한 청국장은 발효 과정 중 대두 단백질의 분해로 생성된 다양한 올리고 펩타이드들이 풍부하게 존재하며, 상기 펩타이드들은 세포 신호 전달에 있어서 중심적 역할을 한다. Bacillus licheniformis B1에 의해 발효된 대두 단백질 유래 펩타이드들은 Ala-Phe-Pro-Gly, Gly-Val-Ala-Trp-Trp-Met-Tyr, Lys-Pro 및 Gln-Lys 등이 있다.MCF7 cells were added to DMEM medium (Dulbecco's Modification of Eagle's medium, Cornig) with 10% Fetal Bovine Serum, 1% antibiotic-antibacterial agent (Caisson), and soybean fermentation extract at 37°C, 5% CO2. Cultured. Soybeans were fermented with Bacillus licheniformis B1, and fermented soybeans were extracted with ethanol to prepare a soybean fermented extract. Cheonggukjang fermented with soybeans is abundantly present in various oligopeptides produced by decomposition of soybean protein during the fermentation process, and the peptides play a central role in cell signal transduction. Peptides derived from soybean protein fermented by Bacillus licheniformis B1 include Ala-Phe-Pro-Gly, Gly-Val-Ala-Trp-Trp-Met-Tyr, Lys-Pro and Gln-Lys.
RNA 프렙(prep) 키트(GeneAll)를 사용하여 RNA를 정제하였다. 0.2 mM dNTP 각각, 0.01 μmol 올리고(oligo) dT, 350 ng RNA 템플레이트(template), 1 유닛(unit) 알엔나제(Rnase) 억제제를 70 ℃에서 10 분간 반응시켰다.RNA was purified using an RNA prep kit (GeneAll). Each of 0.2 mM dNTP, 0.01 μmol oligo dT, 350 ng RNA template, and 1 unit allenase (Rnase) inhibitor were reacted at 70° C. for 10 minutes.
cDNA 합성을 위하여 2 μl RT 완충액, 10 유닛 역전사 효소(Enzynomics)를 혼합물에 첨가하고, 43 ℃에서 90 분 및 70 ℃에서 5 분간 반응시켰다. 정량적 RT PCR이 2X quanti Mix SYBR (Illumina)을 사용하여 수행되었다.For cDNA synthesis, 2 μl RT buffer and 10 units reverse transcriptase (Enzynomics) were added to the mixture, followed by reaction at 43° C. for 90 minutes and 70° C. for 5 minutes. Quantitative RT PCR was performed using 2X quanti Mix SYBR (Illumina).
PLAU 프라이머 시퀀스(primer sequences); A:5'-TCACCACCAAAATGCTGTGT-3'(서열번호 1), B: 5'-AGGCCATTCTCTCTTCCTTGGT-3'(서열번호 2), β-actin A: 5'-CGACTTCGAGCAAGAGATGG-3'(서열번호 3), and B:5'-AGCACTGTGTTGGCGTACAG-3'(서열번호 4).PLAU primer sequences; A:5'-TCACCACCAAAATGCTGTGT-3' (SEQ ID NO: 1), B: 5'-AGGCCATTCTCTCTTCCTTGGT-3' (SEQ ID NO: 2), β-actin A: 5'-CGACTTCGAGCAAGAGATGG-3' (SEQ ID NO: 3), and B :5'-AGCACTGTGTTGGCGTACAG-3' (SEQ ID NO: 4).
PCR 30사이클(95°C에서 15 초간, 55°C에서 30 초간)이 수행되었다.30 cycles of PCR (95°C for 15 seconds, 55°C for 30 seconds) were performed.
ERBB2 프라이머 시퀀스(primer sequences); A: 5'-CAGCCTTGCCCCATCAAC-3'(서열번호 5), B: 5'-GCCCTTGTCATCCAGGTCC-3'(서열번호 6). β-actin A:5'-CGACTTCGAGCAAGAGATGG-3'(서열번호 3), and B: 5'-AGCACTGTGTTGGCGTACAG-3'(서열번호 4). ERBB2 primer sequences; A: 5'-CAGCCTTGCCCCATCAAC-3' (SEQ ID NO: 5), B: 5'-GCCCTTGTCATCCAGGTCC-3' (SEQ ID NO: 6). β-actin A:5'-CGACTTCGAGCAAGAGATGG-3' (SEQ ID NO: 3), and B: 5'-AGCACTGTGTTGGCGTACAG-3' (SEQ ID NO: 4).
PCR 30사이클(95°C에서 15 초간, 55°C에서 30 초간)이 수행되었다.30 cycles of PCR (95°C for 15 seconds, 55°C for 30 seconds) were performed.
MCF7 세포를 0.5 mg/ml 대두 발효 추출물로 1 일 동안 처리하였다. 세포를 NO 형광분석 프로브에 넣고 1.5 시간 동안 저장하였다. 세포 이미지는 FITC 필터가 장착된 형광현미경(DMi8, Leica)을 이용하여 얻었다. 세포의 형광 강도는 Image J 프로그램(국립 보건원)을 사용하여 결정되었다.MCF7 cells were treated with 0.5 mg/ml soybean ferment extract for 1 day. The cells were placed in the NO fluorescence analysis probe and stored for 1.5 hours. Cell images were obtained using a fluorescence microscope (DMi8, Leica) equipped with a FITC filter. The fluorescence intensity of the cells was determined using the Image J program (National Institute of Health).
단백질 - 단백질 상호 작용(PPI) 연결망(네트워크)을 공지의 PPI 데이터베이스를 스캔하여 구축하였다. PPI 데이터를 휴먼 프로틴 레퍼런스 데이터베이스(Human Protein Reference Database, HPRD, http : //www.hprd.org/)에서 다운로드하였다. 상호 작용하는 단백질 쌍(pairs)은 SQLite3 데이터베이스 엔진 (https://www.sqlite.org/)에 저장되었다. 파이썬(Phthon, https://www.python.org/) 구동 스크립트를 사용하여 SQLite3 데이터베이스와 인터페이스하여 PPI 데이터를 검사하였다. A protein-protein interaction (PPI) network (network) was constructed by scanning a known PPI database. PPI data were downloaded from Human Protein Reference Database (HPRD, http: //www.hprd.org/). The interacting protein pairs were stored in the SQLite3 database engine (https://www.sqlite.org/). Using a Python (Phthon, https://www.python.org/) startup script, the PPI data was checked by interfacing with the SQLite3 database.
문헌 조사 및 마이크로어레이 분석에 의하여 선택된 단백질들을 스캔닝을 위한 입력값으로 사용하였다. 만약 하나의 PPI 쌍이 하나의 입력 단백질을 포함한다면 그 상호 작용은 상기 연결망(네트워크)에 포함된다. 상기 상호 작용들이 중복될 경우는 무시된다. 단일 종단의 입력 및 출력 노드를 제거하여 단순화된 연결망(네트워크)의 핵심 사항을 획득하였다(Kim et al., 2011). 상기 상호 작용을 포함하는 그래프를 시각화하고 Cytoscape 프로그램(http://www.cytoscape.org/)을 사용하여 수동으로 편집하였다.Proteins selected by literature search and microarray analysis were used as input values for scanning. If one PPI pair contains one input protein, the interaction is included in the network (network). If the above interactions overlap, it is ignored. The key points of a simplified network (network) were obtained by removing the single-ended input and output nodes (Kim et al., 2011). The graph containing the interaction was visualized and edited manually using the Cytoscape program (http://www.cytoscape.org/).
유방암 MCF7 세포를 대두 발효 추출물로 처리한 후 유의미하게 상이한 수준으로 발현하는 91개의 유전자 리스트를 이전의 연구에서 얻었다((황 외., 2011). 그리고, 전이 핵심 마커로는 ERBB2, MMP1, MMP9, CD9, ADAM9 및 BCL2가 있다. 전이 마커 단백질과 상이하게 발현된 유전자들 간의 상호 작용이 컴바인된 연결망(네트워크)에 확인할 수 있다. 도 1은 컴바인되고 단순화된 연결망(네트워크)을 도시하고 있다.A list of 91 genes expressing significantly different levels after treatment of breast cancer MCF7 cells with soybean fermentation extract was obtained in a previous study ((Hwang et al., 2011), and as key metastasis markers, ERBB2, MMP1, MMP9, CD9, ADAM9 and BCL2 Interactions between the transgenic marker proteins and differently expressed genes can be confirmed in a combined network (network) Fig. 1 shows a combined and simplified network (network).
마이크로 어레이 분석에 있어서 상기 처리후 CASP3 및 PLAU와 같은 암 전이 마커의 유전자 발현 수준이 각각 1.4 배 및 1.3 배 감소하였다(황 외., 2011). CASP3은 연결망(네트워크) 상의 CTNNB1과 KPNB1을 통해 ERBB2와의 상호 작용을 나타낸다(도 1). In microarray analysis, the gene expression levels of cancer metastasis markers such as CASP3 and PLAU decreased 1.4-fold and 1.3-fold, respectively, after the treatment (Hwang et al., 2011). CASP3 represents the interaction with ERBB2 through CTNNB1 and KPNB1 on a network (network) (Fig. 1).
CASP3 및 PLAU 발현의 감소가 전이 과정을 방해할 것으로 예상한다. 몇몇의 단백질들은 단지 마이크로어레이 단백질들만으로 구성된 단백질 상호 연결망(네트워크)에서 유의미한 기능을 나타내지 못 하였다. 그러나, 전이 마커를 포함하는 통합된 상호 연결망(네트워크)은 새로운 단백질 상호작용을 제시하였다. -1.4 배 발현을 보인 CXCL2은 PLG를 통해 MMP9와 상호 작용을 하였다(도 1). CCL3는 MMP 관련 단백질과의 상호 작용에서 중심 역할을 했다(도 1). It is expected that the reduction of CASP3 and PLAU expression will interfere with the metastasis process. Some proteins did not show a significant function in a protein interconnection network (network) consisting of only microarray proteins. However, an integrated interconnection network (network) comprising a transfer marker has revealed a new protein interaction. CXCL2, which showed -1.4 fold expression, interacted with MMP9 through PLG (Fig. 1). CCL3 played a central role in the interaction with MMP-related proteins (Figure 1).
실시예 2: PLAU 및 ERBB2의 발현 억제Example 2: Inhibition of expression of PLAU and ERBB2
암 세포 침습(invasion)은 세포외기질(extracellular matrix, ECM)을 분해하여 달성된다. uPA는 암세포를 분리하여 다른 사이트로의 이동을 유도하는데 관련된다. uPA는 많은 암세포에서 과다 발현되고 전이 과정에서 결정적인 역할을 한다. uPA 과발현은 유방암 및 전이 과정의 좋지 않은 결과와 관련되어 있다(Foekens et al., 2000; Egeblad and Werb, 2002; Vizoso et al., 2007). uPA는 암 줄기세포능(cancer stemness)을 촉진하기 위하여 전사 인자와 상호 작용한다. uPA에 의한 전사 조절은 암 줄기세포능 및 임상적 치사율에 기여한다. 췌장관세포암(PDAC, Pancreatic ductal adenocarcinoma)의 치사는 암줄기세포(cancer stem cell)와 관련이 있다. PDAC의 나쁜 예후는 uPA의 증가된 발현과 관련이 있다. 여기서, 암줄기세포란, 암세포 내에 암을 촉발시키는 시원세포를 의미하는데, 암세포와는 별도로 존재하고, 정상 줄기세포의 특성을 갖고 있는 것으로 알려져 있다.Cancer cell invasion is achieved by degrading the extracellular matrix (ECM). uPA is involved in separating cancer cells and inducing migration to other sites. uPA is overexpressed in many cancer cells and plays a critical role in metastasis. uPA overexpression is associated with poor outcomes in breast cancer and metastasis processes (Foekens et al., 2000; Egeblad and Werb, 2002; Vizoso et al., 2007). uPA interacts with transcription factors to promote cancer stemness. Transcriptional regulation by uPA contributes to cancer stem cell capacity and clinical mortality. The lethality of pancreatic ductal adenocarcinoma (PDAC) is related to cancer stem cells. The poor prognosis of PDAC is associated with increased expression of uPA. Here, the cancer stem cell refers to a progenitor cell that triggers cancer in the cancer cell, which exists separately from the cancer cell and is known to have the characteristics of a normal stem cell.
ERBB2는 상피 성장 인자 수용체(epidermal growth factor receptors, EGFR)를 포함하는 티로신 키나아제 패밀리 중 하나이다. NSLC(None small cell Lung Cancer) 세포 및 유방암 세포는 EGFR의 변이형을 가지고 있거나 과잉 생산되어 있다(Li et al., 2008; Chuang et al., 2017). ERBB2 is one of a family of tyrosine kinases that includes epidermal growth factor receptors (EGFR). NSLC (None small cell Lung Cancer) cells and breast cancer cells have a variant of EGFR or are overproduced (Li et al., 2008; Chuang et al., 2017).
본 발명자들은 유방암 MCF7 세포를 대두 발효 추출물을 처리하고, PLAU 및 ERBB2의 발현 수준을 측정하였다. 놀랍게도, 대두 발효 추출물은 PLAU 및 ERBB2의 발현을 억제하였다(도 2). B. licheniformis B1에 의해 발효된 상기 대두 발효 추출물의 특정 펩타이드들이 PLAU 및 ERBB2의 발현을 억제하는 것으로 보인다.The present inventors treated breast cancer MCF7 cells with soybean fermented extract, and measured the expression levels of PLAU and ERBB2. Surprisingly, the soybean fermented extract inhibited the expression of PLAU and ERBB2 (FIG. 2 ). Certain peptides of the soybean fermented extract fermented by B. licheniformis B1 appear to inhibit the expression of PLAU and ERBB2.
실시예 3: NO 분석Example 3: NO analysis
염증은 전이와 관련된다. 대두 발효 추출물은 전이와 관련된 유전자 발현을 억제하였으므로, 유방암 세포에서 염증 표지자 NO의 생성에 대두 발효 추출물의 영향을 분석하였다. 대두 발효 추출물로 처리한 암 세포에서 NO 생성은 현저하게 감소하였다(도 3).Inflammation is associated with metastasis. Since the soybean fermented extract inhibited metastasis-related gene expression, the effect of the soybean fermented extract on the production of NO, an inflammation marker in breast cancer cells was analyzed. NO production was significantly reduced in cancer cells treated with the soybean fermented extract (FIG. 3).
한편, 이상의 상세한 설명은 모든 면에서 제한적으로 해석되어서는 아니되고 예시적인 것으로 고려되어야 한다. 본 발명의 범위는 첨부된 청구항의 합리적 해석에 의해 결정되어야 하고, 본 발명의 등가적 범위 내에서의 모든 변경은 본 발명의 범위에 포함된다.On the other hand, the above detailed description should not be construed as restrictive in all respects and should be considered as illustrative. The scope of the present invention should be determined by rational interpretation of the appended claims, and all changes within the equivalent scope of the present invention are included in the scope of the present invention.
Claims (9)
A pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer, comprising as an active ingredient a fermented soybean extract that inhibits the expression or activity of PLAU (plasminogen activator, urokinase) protein and ERBB2 (epidermal growth factor receptor 2) protein.
A pharmaceutical composition for preventing, treating, or inhibiting metastasis of breast cancer, comprising an inhibitor of the expression or activity of a PLAU (plasminogen activator, urokinase) protein as an active ingredient.
상기 대두 발효 추출물은 Bacillus licheniformis 균주로 대두를 발효시킨 추출물인 것을 특징으로 하는 유방암의 예방, 치료 또는 전이억제용 약학적 조성물.
The method of claim 1,
The soybean fermentation extract is a pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer, characterized in that the soybean is fermented with Bacillus licheniformis strain.
상기 대두 발효 추출물은 Bacillus licheniformis 균주로 대두를 발효시킨 대두 발효물을 에탄올로 추출하여 제조된 청국장 추출물이고,
상기 대두 발효 추출물은 Ala-Phe-Pro-Gly, Gly-Val-Ala-Trp-Trp-Met-Tyr, Lys-Pro 및 Gln-Lys 으로 이루어진 군 중에서 1종 이상 선택되는 펩타이드를 포함하는 것을 특징으로 하는 유방암의 예방, 치료 또는 전이억제용 약학적 조성물.
The method of claim 1,
The soybean fermentation extract is a cheonggukjang extract prepared by extracting a fermented soybean fermented soybean with Bacillus licheniformis strain with ethanol,
The soybean fermentation extract comprises a peptide selected from the group consisting of Ala-Phe-Pro-Gly, Gly-Val-Ala-Trp-Trp-Met-Tyr, Lys-Pro, and Gln-Lys. A pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer.
상기 조성물이 유방암 세포의 성장 억제 및 전이(metastasis) 억제 효과를 갖는 것을 특징으로 하는 유방암의 예방, 치료 또는 전이억제용 약학적 조성물.
The method according to claim 1 or 2,
The pharmaceutical composition for preventing, treating or inhibiting metastasis of breast cancer, characterized in that the composition has an effect of inhibiting the growth of breast cancer cells and inhibiting metastasis.
A food composition for preventing, improving or inhibiting metastasis of breast cancer, comprising as an active ingredient a soybean ferment extract that inhibits the expression or activity of PLAU (plasminogen activator, urokinase) protein and ERBB2 (epidermal growth factor receptor 2) protein.
상기 대두 발효 추출물은 Bacillus licheniformis B1 균주로 대두를 발효시킨 추출물인 것을 특징으로 하는 유방암의 예방, 개선 또는 전이억제용 식품 조성물.
The method of claim 6,
The soybean fermentation extract is a food composition for preventing, improving or inhibiting metastasis of breast cancer, characterized in that the soybean is fermented with Bacillus licheniformis B1 strain.
A method for treating or inhibiting metastasis of breast cancer comprising: administering a soybean ferment extract that inhibits the expression or activity of PLAU (plasminogen activator, urokinase) protein and ERBB2 (epidermal growth factor receptor 2) protein to individuals other than humans.
상기 대두 발효 추출물은 Bacillus licheniformis B1 균주로 대두를 발효시킨 대두 발효물을 에탄올로 추출하여 제조된 청국장 추출물인 것을 특징으로 하는 유방암의 치료 또는 전이 억제 방법.The method of claim 8,
The soybean fermentation extract is a method for treating or inhibiting metastasis of breast cancer, characterized in that the soybean fermentation product obtained by fermenting soybeans with Bacillus licheniformis B1 strain is extracted with ethanol.
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| KR (1) | KR102283767B1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030008023A1 (en) * | 2001-03-21 | 2003-01-09 | Kung-Ming Lu | Methods for inhibiting cancer growth, reducing infection and promoting general health with a fermented soy extract |
| KR100909998B1 (en) | 2007-03-29 | 2009-07-29 | 주식회사 인섹트 바이오텍 | Pharmaceutical composition for breast cancer prevention and treatment with arazyme as an active ingredient |
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2019
- 2019-06-04 KR KR1020190065726A patent/KR102283767B1/en active IP Right Grant
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030008023A1 (en) * | 2001-03-21 | 2003-01-09 | Kung-Ming Lu | Methods for inhibiting cancer growth, reducing infection and promoting general health with a fermented soy extract |
| KR100909998B1 (en) | 2007-03-29 | 2009-07-29 | 주식회사 인섹트 바이오텍 | Pharmaceutical composition for breast cancer prevention and treatment with arazyme as an active ingredient |
Non-Patent Citations (1)
| Title |
|---|
| 호서대학교대학원. 석사학위논문. 송혜정. (2011.02.)* * |
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| KR102283767B1 (en) | 2021-08-02 |
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