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).
Highlights
Epithelial ovarian cancer (EOC) is one of the leading causes of cancer-related deaths in women, and the most lethal gynecologic malignancy[1]
These results suggest that c-MET inhibitor is more effective in ovarian clear cell carcinoma (OCCC) cells that contain high c-MET expression
Yamashita et al reported that MET knockdown by short-hairpin RNA resulted in a decline of cell viability in MET-amplified OCCC cell lines due to increased apoptosis and senescence, suggesting that the MET signaling pathway plays an important role in OCCC carcinogenesis[19]
Summary
Epithelial ovarian cancer (EOC) is one of the leading causes of cancer-related deaths in women, and the most lethal gynecologic malignancy[1]. In EOC, overexpression of c-MET is found in about 7% to 27%15–18 and it is associated with ovarian cancer progression and adverse outcomes[17,18]. Several in vitro and in vivo studies reported that inhibition of c-MET using small interfering RNA and small molecule inhibitors reduced EOC growth and metastasis[16,17,20,21], the therapeutic effects of c-MET inhibitors in patients with OCCC have seldom been addressed. The present study, we investigated the effects of c-MET inhibitors in OCCCs with in vivo as well as in vitro experiments including an orthotopic mouse model using an established cell line (RMG1) and a patient-derived tumor xenograft (PDX) model
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