Abstract 4299: MicroRNA 200c regulates cytochrome P450 1B1-mediated docetaxel resistance in renal cell cancers

Abstract

Abstract Cytochrome P450 1B1 (CYP1B1) is up-regulated in many types of cancer. It has been suggested that CYP1B1 may be a general tumor biomarker and have an important function in cancers. Despite its high protein expression and enzymatic activity in renal cell cancer (RCC), functional significance of CYP1B1 has not been elucidated. Here we explored the functional role and regulatory mechanism of CYP1B1 in RCC. Reduction of CYP1B1 levels fail to prevent in vitro tumorigenicity such as proliferation, apoptosis, and cell cycle progression of RCC cells. Moreover, the expression levels are not associated with tumor type, stage, Fuhrman grade and 5-year survival probability after surgery. Instead, alteration of CYP1B1 expression regulates the chemosensitivity of RCC cells to docetaxel suggesting its critical contribution to the RCC chemoresistance. Additionally, miR-200c, which is significantly down-regulated in RCC tissues and cell lines regulates CYP1B1 mRNA, protein and enzyme activity. An inverse association was also observed between the expression levels of miR-200c and CYP1B1 protein in RCC tissues. Thus, high expression of CYP1B1 could be a result of decreased miR-200c expression in RCC. Finally, alteration of miR-200c levels affects the chemosensitivity of RCC cells. Restoration of docetaxel resistance by exogenous expression of CYP1B1 in miR-200c-over-expressing cells indicates that CYP1B1 is a functional target of miR-200c. These results suggest that CYP1B1 up-regulation mediated by low miR-200c is one of the mechanisms underlying resistance of RCC cells to docetaxel. Therefore, expression of CYP1B1 and miR-200c in RCC may be useful as a prediction for docetaxel response. Citation Format: Inik Chang, Yozo Mitsui, Shinichiro Fukuhara, Ankurpreet Gill, Darryn K. Wong, Soichiro Yamamura, Varahram Shahryari, Z. Laura Tabatabai, Rajvir Dahiya, Dong Min Shin, Yuichiro Tanaka. MicroRNA 200c regulates cytochrome P450 1B1-mediated docetaxel resistance in renal cell cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4299. doi:10.1158/1538-7445.AM2015-4299