Loss of miR-200c up-regulates CYP1B1 and confers docetaxel resistance in renal cell carcinoma

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

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36 Citations (Scopus)

Abstract

Despite high protein expression and enzymatic activity of cytochrome P450 1B1 (CYP1B1) in renal cell cancer (RCC), its functional significance 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 chemoresistance. Additionally, miR-200c, which is significantly down-regulated in RCC regulates CYP1B1 expression and activity. An inverse association was also observed between the expression levels of miR-200c and CYP1B1 protein in RCC tissues. 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.

Original languageEnglish
Pages (from-to)7774-7787
Number of pages14
JournalOncotarget
Volume6
Issue number10
DOIs
Publication statusPublished - 2015

All Science Journal Classification (ASJC) codes

  • Oncology

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    Chang, I., Mitsui, Y., Fukuhara, S., Gill, A., Wong, D. K., Yamamura, S., Shahryari, V., Laura Tabatabai, Z., Dahiya, R., Shin, D. M., & Tanaka, Y. (2015). Loss of miR-200c up-regulates CYP1B1 and confers docetaxel resistance in renal cell carcinoma. Oncotarget, 6(10), 7774-7787. https://doi.org/10.18632/oncotarget.3484