Introduction/Background FBXW7, a tumor suppressor gene plays a critical role in cell cycle progression under the regulation of the transcription factor E2F5. While FBXW7 is silenced in several cancers; its role in ovarian cancer pathogenesis is still unclear. This study explored FBXW7 promotor methylation status in ovarian cancer and its functional significance.
Methodology FBXW7 expression at mRNA and protein levels were assessed in OVSAHO and MCAS cells using RT-qPCR and western blotting respectively. Expression of FBXW7 was high in MCAS and low in OVSAHO cells. FBXW7 gene methylation status was analyzed in cell lines (MCAS & OVSAHO) as well as in 23 EOC patients (5 normal, 8 benign, 4 borderline, 5 high grade tumors) by both methylation-specific PCR and MS-HRM analysis.
Results In addition to OVSAHO cells, more than 60% of patients analyzed showed methylation. To evaluate its functional importance, FBXW7 expression was restored in OVSAHO cells by treatment with the demethylation agent, 5’-aza-2’deoxycitidine. Western blotting in FBXW7-restored OVSAHO cells and FBXW7-positive cell line (MCAS) showed an upregulation in caspases-2, 3, 7, BAX, P53, BAD, Cyclin D1, pNFkB and pGSK3-beta, whereas Bcl-2, Bcl-x, pBad, STAT3, GSK3-beta and NFkB were downregulated; indicating cells to undergo apoptosis via STAT3 pathway.
Conclusion This study described an alternative mechanism for FBXW7 inactivation, namely promoter specific methylation in ovarian cancer and identified FBXW7 as a potential target for guiding the development of therapeutic strategies against ovarian cancer.
Disclosure Nothing to disclose.
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