Loss of miR-200c up-regulates CYP1B1 and confers docetaxel resistance in renal cell carcinoma
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Inik Chang1,2,*, Yozo Mitsui1,3,*, Shinichiro Fukuhara1,3, Ankurpreet Gill1, Darryn K. Wong1, Soichiro Yamamura1,3, Varahram Shahryari1, Z. Laura Tabatabai4, Rajvir Dahiya1,3, Dong Min Shin2 and Yuichiro Tanaka1,3
1 Department of Surgery and Division of Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America
2 Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
3 Department of Urology, University of California, San Francisco, California, United States of America
4 Department of Pathology, Veterans Affairs Medical Center and University of California, San Francisco, California, United States of America
* These authors are equally contributed to this work
Inik Chang, email:
Yuichiro Tanaka, email:
Keywords: Renal cell carcinoma, CYP1B1, miR-200c, chemotherapy, docetaxel
Received: November 19, 2014 Accepted: February 04, 2015 Published: March 08, 2015
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.
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