miR-433 accelerates acquired chemoresistance of gallbladder cancer cells by targeting cyclin M.

Resistance to chemotherapy is associated with dismal prognosis in patients with gallbladder cancer. Cyclin-dependent kinase 10 (CDK10) influences the chemosensitivity of gallbladder cancer cells, and cyclin M is the activating factor and binding partner of CDK10. To determine the effect of CDK10 or cyclin M overexpression on chemosensitivity, gemcitabine-resistant (GR) subclones were established from CDK10 or cyclin M stable transfectants. Stable overexpression of CDK10 increased the sensitivity to gemcitabine in non-resistant cells and did not further increase the sensitivity to gemcitabine in the GR subclones. GR subclones exhibited a significantly decreased expression of cyclin M while maintaining the expression levels of CDK10, compared with the non-resistant cells. MicroRNA (miR)-433 was identified as a candidate factor involved in the mechanism of the downregulation of M cyclin in GR subclones. Luciferase assays confirmed the interaction between miR-433 and the 3' untranslated region (3'UTR) of cyclin M. Additionally, ectopic expression of miR-433 significantly decreased the expression of cyclin M. Finally, increased expression of circulating miR-433 was associated with poor outcome of chemotherapy. The results of the present study suggest that miR-433 is a potential biomarker for evaluating chemosensitivity in gallbladder cancer.