MicroRNA-494 sensitizes colon cancer cells to fluorouracil through regulation of DPYD

• Published in: IUBMB life Vol. 67; no. 3; p. 191
• Main Authors: Chai, Jie, Dong, Wei, Xie, Chao, Wang, Lin, Han, Da-Li, Wang, Shan, Guo, Hong-Liang, Zhang, Zong-Li
• Format: Journal Article
• Language: English
• Published: England 01.03.2015
• Subjects: 3' Untranslated Regions; Animals; Antimetabolites, Antineoplastic - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Cell Line, Tumor - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Dihydrouracil Dehydrogenase (NADP) - genetics; Dihydrouracil Dehydrogenase (NADP) - metabolism; Drug Resistance, Neoplasm - genetics; Female; Fluorouracil - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Xenograft Model Antitumor Assays; chemoresistance; miR-494; colon cancer; DPYD; microRNA; fluorouracil; chemosensitivity
• ISSN: 1521-6551
• DOI: 10.1002/iub.1361

Chemoresistance of colon cancer cells to the chemotherapeutics is still a main obstacle in treatment of this malignancy. The microRNA (miRNA) mediated chemosensitivity regulation in colon cancer cells is still largely unknown. Here we constructed a fluorouracil (5-Fu) resistant SW480 cell line (SW480/5-Fu) and discovered that miRNA miR-494 was down-regulated in the drug resistant cells compared with the parental cells. miR-494 level was found to be correlated with 5-Fu sensitivity in colon cancer cells, and artificial alteration of miR-494 affects the sensitivity of colon cancer cell lines to 5-Fu. miR-494 also promoted apoptosis of colon cancer cells at present of 5-Fu. Importantly, as a regulatory enzyme in the 5-Fu catabolic pathway, DPYD was confirmed to be a direct target of miR-494 through the interaction of miR-494 and its binding site within DPYD 3' untranslated region (3'UTR). miR-494 also negatively regulated endogenous DPYD expression in SW480 cells. Overexpression or knockdown of DPYD could attenuate miR-494 mediated 5-Fu sensitivity regulation, suggesting the dependence of DPYD regulation in miR-494 activity. miR-494 inhibited SW480/5-Fu derived xenograft tumors growth in vivo at present of 5-Fu. Thus, we concluded that in colon cancer cells, tumor suppressor miR-494 enhanced 5-Fu sensitivity via regulation of DPYD expression.