| Summary: | 碩士 === 國立中正大學 === 生命科學系暨分子生物研究所暨生物醫學研究 === 97 === Ovarian cancer is one of the ten leading causes of cancer death among women. Multiple genetic and epigenetic alterations play important roles in ovarian carcinogenesis. Moreover, aberrant TGF-β signaling pathway is recently demonstrated to be crucial for development of ovarian cancer. Such signaling dysregulation can mediate epigenetic silencing of downstream targets of the signaling pathway.
In our previous study, using chromatin immunoprecipitation microarray coupled with expression microarray, RunX1T1 was identified as a Smad4 target in normal ovarian surface epithelial, IOSE cells. In the current study, we first confirmed that transcription of RunX1T1 is positively regulated by Smad4. Moreover, expression of RunX1T1 was down-regulated in ovarian cancer cells through DNA methylation and histone modification. In demethylated MCP3 cells, knockdown of Smad4 accelerated re-silencing of RunX1T1 through faster re-methylation of the promoter. On the other hand, restoration of RunX1T1 inhibited tumor growth in vitro. Moreover, methylation of RunX1T1 was significantly associated with higher stage tumor in 95 ovarian cancer patients. Interestingly, methylation status of RunX1T1 and another TGF-β/Smad4 target gene, FBXO32, was significantly correlated in those samples. Lastly, methylation of RunX1T1 was detected in ovarian cancer initiating cells (OCIC) thus suggesting that methylation of RunX1T1 is crucial for ovarian carcinogenesis. In conclusion, dysregulation of TGF-β/Smad4 signaling pathway may lead to epigenetic silencing of RunX1T1 in ovarian cancer cells. Patients showing concurrent hypermethylation of RunX1T1 and FBXO32 may be due to signaling dysregulation in those samples and that methylation of RunX1T1 may be able to serve as a novel prognostic indicator in ovarian cancer.
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