title: MicroRNA-494 sensitizes colon cancer cells to fluorouracil through regulation of DPYD.
abstract: 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.
authors: Department of General Surgery, Shandong Cancer Hospital and Institute, Jinan, China.
authors: Jie
authors: J
authors: Chai
authors: Wei
authors: W
authors: Dong
authors: Chao
authors: C
authors: Xie
authors: Lin
authors: L
authors: Wang
authors: Da-Li
authors: DL
authors: Han
authors: Shan
authors: S
authors: Wang
authors: Hong-Liang
authors: HL
authors: Guo
authors: Zong-Li
authors: ZL
authors: Zhang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; C547168:MIRN494 microRNA, human; D035683:MicroRNAs; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: DPYD; chemoresistance; chemosensitivity; colon cancer; fluorouracil; miR-494; microRNA