US20210018505A1 - Marker composition for diagnosing or predicting prognosis of lung cancer based on exosome overexpressing gcc2 gene or protein - Google Patents

Marker composition for diagnosing or predicting prognosis of lung cancer based on exosome overexpressing gcc2 gene or protein Download PDF

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US20210018505A1
US20210018505A1 US16/762,140 US201816762140A US2021018505A1 US 20210018505 A1 US20210018505 A1 US 20210018505A1 US 201816762140 A US201816762140 A US 201816762140A US 2021018505 A1 US2021018505 A1 US 2021018505A1
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protein
lung cancer
kit
exosome
gcc2
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Hyun Koo Kim
Sung Hoi Hong
Yong Park
Yeon Ho Choi
Ji Ho Park
Byeong Hyeon CHOI
Hye Sun JEONG
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Korea Advanced Institute of Science and Technology KAIST
Korea University Research and Business Foundation
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Korea Advanced Institute of Science and Technology KAIST
Korea University Research and Business Foundation
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3023—Lung
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57423—Specifically defined cancers of lung
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the following description relates to a marker composition for diagnosing or prognosing lung cancer based on exosomes overexpressing a GCC2 gene or protein.
  • a tumor is a product of uncontrolled and disordered cell proliferation resulting from abnormal cell excess.
  • the tumor has disruptive proliferative, invasive and metastatic properties, the tumor is classified as a malignant tumor, that is, a cancer.
  • examination means for diagnosing cancer includes methods using X-ray imaging, endoscopy, biopsy, and the like.
  • these methods are relatively simple, the diagnosis success thereof is not high or the hygiene problem occurs. Further, a patient undergoes a pain in a process of the examination. Thus, a diagnosis method of cancer to replace the above methods is required.
  • the diagnosis of cancer with high sensitivity and specificity is important in a pre-treatment stage. Only when the cancer is detected in an early stage thereof via the diagnosis, a cure success of the cancer is high.
  • the present disclosure is to solve the above-mentioned problems of the prior art.
  • a purpose of the present disclosure is to provide a marker composition that may be used in a non-invasive way while improving accuracy of lung cancer diagnosis.
  • a marker composition for diagnosing or prognosing lung cancer, the composition containing exosome overexpressing a GCC2 (GRIP and coiled-coil domain-containing protein) gene or protein.
  • GCC2 GRIP and coiled-coil domain-containing protein
  • compositions for diagnosing or prognosing lung cancer containing a primer or a probe that specifically binds to a GCC2 (GRIP and coiled-coil domain-containing protein) gene in exosome.
  • GCC2 GRIP and coiled-coil domain-containing protein
  • compositions for diagnosing or prognosing lung cancer containing an antibody that specifically binds to a GCC2 (GRIP and coiled-coil domain-containing protein) protein in exosome.
  • GCC2 GRIP and coiled-coil domain-containing protein
  • a kit for diagnosing or prognosing lung cancer, the kit containing the composition.
  • the kit may be one or more selected from a group consisting of an RT-PCR kit, a microarray chip kit, a DNA kit and a protein chip kit.
  • a method for providing information needed to diagnose or prognose lung cancer including (a) separating an exosome from a biological sample; and (b) measuring an expression level of GCC2 (GRIP and coiled-coil domain-containing protein) gene or protein in the exosome.
  • GCC2 GRIP and coiled-coil domain-containing protein
  • the biological sample may be one or more selected from a group consisting of whole blood, serum, plasma, saliva, urine, sputum, lymph and cell.
  • a method for screening a lung cancer therapeutic agent including (a) treating a biological sample collected from a lung cancer patient with a candidate substance for a lung cancer therapeutic agent; (b) separating exosome from the biological sample; and (c) measuring an expression level of GCC2 (GRIP and coiled-coil domain-containing protein) gene or protein in the exosome.
  • GCC2 GRIP and coiled-coil domain-containing protein
  • the marker composition in accordance with the present disclosure contains gene or protein that is overexpressed in exosome of a lung cancer patient. Measuring the expression level thereof may allow diagnosing or prognosing the lung cancer in a non-invasive manner and at a high accuracy.
  • FIG. 1 shows the results of measuring the GCC2 gene expression level in the exosome according to an embodiment of the present disclosure.
  • FIG. 2 shows the results of measuring the exosome secretion according to an embodiment of the present disclosure.
  • FIG. 3 is a standard curve calculated for quantification of GCC2 protein in the exosome according to an embodiment of the present disclosure.
  • FIG. 4 shows the results of measuring the GCC2 protein expression level in the exosome according to an embodiment of the present disclosure.
  • FIG. 5 shows the results of Western blot measurement of the GCC2 protein expression level in the exosome according to an embodiment of the present disclosure.
  • FIG. 6 shows the ELISA results of measuring the GCC2 protein expression level in the exosome according to an embodiment of the present disclosure.
  • FIG. 7 shows the ELISA results of measuring the GCC2 protein expression level in the exosome based on the stages of cancer progression according to an embodiment of the present disclosure.
  • a marker composition for diagnosing or prognosing lung cancer, the composition containing exosome overexpressing a GCC2 (GRIP and coiled-coil domain-containing protein) gene or protein.
  • GCC2 GRIP and coiled-coil domain-containing protein
  • exosome overexpressing a GCC2 gene or protein refers to exosome that expresses a higher level of the GCC2 gene or protein than exosome present in normal cells expresses.
  • exosome refers to a nano-sized small endoplasmic reticulum (30 to 150 nm) secreted from most of cells.
  • the exosomes and phospholipid bilayer are known to contain various kinds of proteins, genetic materials (DNA, mRNA, miRNA), lipids, etc. derived from cells. Further, it has been reported that exosomes derived from tissues may be used to diagnose diseases because the exosomes derived from the tissues reflect the state of the tissues secreting the exosomes.
  • the present inventors confirmed that using the GCC2 gene or protein specifically expressed from lung cancer-derived exosomes may allow accurately and quickly diagnosing or prognosing the lung cancer. In this way, the present disclosure has been completed.
  • diagnosis refers to identifying the presence or characteristic of a pathological condition, that is, whether the lung cancer occurs.
  • prognosis refers to determining the recurrence, metastasis, drug responsiveness, and resistance of the subject after treatment of lung cancer.
  • the “prognosis” may include measuring the expression level of GCC2 in the exosomes isolated from the subject's sample, thereby to not only predict whether the subject has lung cancer, but also predict whether the subject is likely to have a good survival prognosis in the future.
  • the lung cancer may be diagnosed or prognosed based on the measuring result of the expression level of the GCC2 gene or protein, primers or probes that specifically bind to the gene, or antibodies that specifically bind to the protein may be used as the composition for diagnosing or prognosing the lung cancer.
  • kits for diagnosing or prognosing lung cancer may be provided by applying a primer or a probe specifically binding to the GCC2 gene, or an antibody specifically binding to the GCC2 protein to a kit.
  • the kit may include, but is not limited to, an RT-PCR kit, a microarray chip kit, a DNA kit, a protein chip kit, and the like.
  • the kit may check and detect the expression level in the exosome of the GCC2 gene or protein corresponding to the marker to diagnose or prognose lung cancer based on the expression level.
  • the kit may include primers, probes or antibodies that selectively recognize markers for the diagnosis or prognosis of lung cancer, as well as one or more other component compositions, solutions, or devices suitable for analytical methods.
  • the kit may include a substrate, a suitable buffer solution, a secondary antibody labeled with a chromogenic enzyme or a fluorescent substance, and a chromogenic substrate for immunological detection of the antibody.
  • the substrate may include a nitrocellulose membrane, a 96 well plate synthesized with a polyvinyl resin, a 96 well plate synthesized with a polystyrene resin, a slide glass made of glass, and the like.
  • the chromogenic enzyme may include peroxidase, alkaline phosphatase, etc.
  • the fluorescent substance may include FITC, RITC, etc.
  • the chromogenic substrate may include ABTS (2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid)) or OPD (O-phenylenediamine), TMB (tetramethyl benzidine).
  • a method of providing information necessary for diagnosing or prognosing lung cancer includes (a) separating an exosome from a biological sample; and (b) measuring an expression level of a GCC2 (GRIP and coiled-coil domain-containing protein) gene or protein in the exosome.
  • GCC2 GRIP and coiled-coil domain-containing protein
  • the biological sample may be one or more selected from a group consisting of whole blood, serum, plasma, saliva, urine, sputum, lymph, and cells, preferably, whole blood or cells.
  • the present disclosure is not limited thereto.
  • the gene expression level measurement includes a process of identifying the presence and the expression level of mRNA of the GCC2 gene in a biological sample for diagnosing or prognosing the lung cancer, and may mean measuring mRNA expression level.
  • Analytical methods for the gene expression level measurement may include reverse transcriptase PCR (RT-PCR), competitive reverse transcriptase PCR (Competitive RT-PCR), real-time reverse transcriptase (Real-time RT-PCR), RNase protection assay (RPA), northern blotting, DNA chips and the like, but is not limited thereto.
  • RT-PCR reverse transcriptase PCR
  • Competitive RT-PCR competitive reverse transcriptase PCR
  • Real-time RT-PCR real-time reverse transcriptase
  • RNase protection assay RNase protection assay
  • northern blotting DNA chips and the like, but is not limited thereto.
  • the protein expression level measurement refers to a process of identifying the presence and the expression level of the GCC2 protein in a biological sample for diagnosing or prognosing the lung cancer.
  • the expression level measurement or comparative analysis method of the protein may include protein chip analysis, immunoassay, ligand binding assay, Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF), and Surface Enhanced Laser Desorption/Ionization Time of Flight Mass Spectrometry (SELDI-TOF), radioimmunoassay, radial immunodiffusion, Ouchterlony immunodiffusion, rocket immunoelectrophoresis, tissue immunostaining, complement fixation analysis, two-dimensional electrophoresis, liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), western blotting, and enzyme-linked immunosorbentassay (ELISA), and the like, but is not limited thereto.
  • MALDI-TOF Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry
  • SELDI-TOF Surface Enhanced
  • the gene or protein expression level of the GCC2 is measured and then when the expression level is higher than that of a normal control group, it may be determined that the lung cancer has occurred or is more likely to occur.
  • a method for screening a lung cancer therapeutic agent including (a) treating a biological sample collected from a lung cancer patient with a candidate substance for a lung cancer therapeutic agent; (b) separating exosome from the biological sample; and (c) measuring an expression level of a GCC2 (GRIP and coiled-coil domain-containing protein 2) gene or protein in the exosome.
  • GCC2 GRIP and coiled-coil domain-containing protein 2
  • the process of screening the candidate substance for the lung cancer therapeutic agent may be applied. That is, after treating the biological sample isolated from a lung cancer patient with the candidate substance for the lung cancer therapeutic agent, and then when the expression level of the GCC2 gene or protein in the exosome present in the biological sample decreases, it may be identified that the candidate substance effectively functions as the lung cancer therapeutic agent.
  • Each of five lung cancer cell lines (H522, A549, H1650, PC9, H1299) was cultured in a dish of 150 mm in diameter.
  • FBS Fetal Bovine Serum
  • the culture solution was used to continuously culture the cell lines for 2 to 3 days so that the cells were brought into a 70 to 80% confluency state.
  • the obtained culture solution was centrifuged at 10,000 g for 30 minutes to remove cell debris, and sequentially passed through 0.45 ⁇ m and 0.22 ⁇ m filters to remove relatively bulky materials.
  • the filtered cell culture solution was then concentrated using Amicon tube 100K (Millipore, USA) while leaving only particles of the desired size.
  • RIPA lysis buffer (Thermo Fisher Scientific, USA) was applied to the concentrated exosome to obtain protein, which was commissioned to the Korea Basic Science Institute (KBSI) to obtain protein analysis results.
  • GCC2 GRIP and coiled-coil domain-containing protein
  • RT-PCR reverse transcription polymerase chain reaction
  • qRT-PCR was performed three times using a KAPA SYBR FAST qPCR Master Mix (2 ⁇ ) kit on a StepOne Plus Real-Time PCR System (Applied Biosystems, CA) according to the manufacturer's instructions.
  • the base sequences of the primer pairs used in the reaction are shown in Table 1 below, and the results of qRT-PCR are shown in FIG. 1 .
  • GCC2 is a protein that is estimated to be related to exosome production
  • exosome secretion was measured in normal cell lines (HPAECs) and lung cancer cell lines (H1299, H522). Exosome secretion was measured indirectly using DLS (Dynamic Light Scattering).
  • the cell lines were exposed to the culture solution of 1.5 ml for 24 hours. Then, only the exosome was separated from 1 ml of the culture solution without concentration, and then a count rate was measured using DLS. The presence of a large number of particles in the solution increases the count rate. This allows indirect comparison between the amounts of exosomes in the cell lines. Further, the particle amount was calculated based on an average obtained by dividing the count rate based on the number of cells at the time when the culture solution was collected. The results are shown in Table 2 and FIG. 2 below.
  • the lung cancer cell line has a larger amount of particles than that of the normal cell line. This means that the lung cancer cell line has more active exosome secretion than the normal cell line has. Based on these results, it may be expected that the GCC2 expressed only in exosome of the lung cancer cell line affects exosome secretion.
  • exosomes were extracted from the lung cancer cell lines and normal cell lines using RIPA lysis buffer containing a proteinase inhibitor cocktail, and each of the exosomes was lysed to obtain protein.
  • the obtained protein was quantified using the Bradford assay method.
  • the proteins obtained from the exosomes were diluted at a 1:100 ratio and were quantified. OD values as shown in Table 3 below were obtained.
  • the concentrations of HPAECs, H1299, and H522 were calculated to be 1013.574 ⁇ g/ml 2318.93 ⁇ g/ml and 2137.177 ⁇ g/ml, respectively. Based on this result, a sample was prepared by inactivating each of 20 ⁇ g of protein obtained from cells and 15 ⁇ g of protein obtained from exosomes with heat.
  • Total protein lysates were loaded on 10% SDS-PAGE gel on a lane basis and fractionated based on a size.
  • the separated protein was attached to a PVDF membrane and blocked with tris-buffered saline-Tween 20 containing 5% skim milk.
  • the PVDF membrane was treated overnight at 4 with GCC2 (1:500, Santa Cruz), CD63 (1:500, Santa Cruz), ⁇ -tubulin (1:500, Santa Cruz) primary antibodies. Then, the PVDF membrane was treated with anti-rabbit IgG-HRP binding secondary antibody, and then was washed and reacted with ECL buffer (Bio-rad, USA). Images obtained using FluorChem E system (proteinsimple, USA) are shown in FIG. 4 .
  • the cell lysate showed no difference between GCC2 protein expression levels in the normal cell line and lung cancer cell line, but the exosome lysate showed a similar pattern to that of CD63 as an exosome marker.
  • the protein percentages in the normal cells and lung cancer cells in the same amount of the protein are not equal to each other, and the GCC2 protein shows a similar tendency to that of the exosome marker CD63. That is, it was identified that the cancer cells have a protein percentage different from that in the normal cells, and in particular, the GCC2 is strongly expressed in the cancer cells.
  • the GCC2 showed low sensitivity in early lung cancer (T1N0) and showed high sensitivity in the stage 3 cancer (T3N0).
  • the sensitivity increased significantly in the metastatic cancer state compared to the normal state ( FIG. 7 ).

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CN113785200A (zh) 2019-04-03 2021-12-10 高丽大学校产学协力团 基于过表达tuba1c蛋白的外泌体的诊断癌症或预测预后的标志物组合物
KR102318328B1 (ko) * 2020-04-13 2021-10-27 고려대학교 산학협력단 Gcc2 단백질을 과발현하는 엑소좀 기반 암 진단 또는 예후 예측용 마커 조성물
KR20230084704A (ko) 2021-12-06 2023-06-13 주식회사 엑소퍼트 Gcc2 억제제를 유효성분으로 포함하는 폐암 예방 또는 치료용 조성물
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