title: c-MET as a Potential Therapeutic Target in Ovarian Clear Cell Carcinoma.
abstract: In this study, we investigated the therapeutic effects of c-MET inhibition in ovarian clear cell carcinoma (OCCC). Expression levels of c-MET in the epithelial ovarian cancers (EOCs) and normal ovarian tissues were evaluated using real-time PCR. To test the effects of c-MET inhibitors in OCCC cell lines, we performed MTT and apoptosis assays. We used Western blots to evaluate the expression of c-MET and its down-stream pathway. In vivo experiments were performed to test the effects of c-MET inhibitor on tumor growth in orthotopic mouse xenografts of OCCC cell line RMG1 and a patient-derived tumor xenograft (PDX) model of OCCC. c-MET expression was significantly greater in OCCCs compared with serous carcinomas and normal ovarian tissues (p < 0.001). In in vitro study, inhibition of c-MET using c-MET inhibitors (SU11274 or crizotinib) significantly decreased the proliferation, and increased the apoptosis of OCCC cells. SU11274 decreased expression of the p-c-MET proteins and blocked the phosphorylation of down-stream proteins Akt and Erk. Furthermore, SU11274 treatment significantly decreased the in vivo tumor weight in xenograft models of RMG1 cell and a PDX model for OCCC compared to control (p = 0.004 and p = 0.009, respectively).
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Wonkwang Medical Science, College of Medicine, Wonkwang University, Iksan, Korea.
authors.forename: Ha-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Aera
authors.initials: A
authors.lastname: Yoon
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Ryu
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Young-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jung-Joo
authors.initials: JJ
authors.lastname: Choi
authors.affiliation: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Song
authors.affiliation: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Heejin
authors.initials: H
authors.lastname: Bang
authors.affiliation: Health promotion center Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ji Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong.
authors.forename: William Chi
authors.initials: WC
authors.lastname: Cho
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Chel Hun
authors.initials: CH
authors.lastname: Choi
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.|Samsung Advanced Institute for Health Sciences &Technology, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jeong-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Byoung-Gie
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Duk-Soo
authors.initials: DS
authors.lastname: Bae
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077547:Crizotinib; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D007211:Indoles; D009363:Neoplasm Proteins; D010879:Piperazines; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met