title: miR-203 enhances chemosensitivity to 5-fluorouracil by targeting thymidylate synthase in colorectal cancer.
abstract: MicroRNAs (miRNAs) are a conserved class of small non-coding RNAs that play important roles in diverse biological processes, including chemoresistance. However, the molecular mechanism as to how miR-203 modulates the chemosensitivity to 5-fluorouracil (5-FU) in colorectal cancer is poorly known. In the present study, we found that miR-203 was downregulated in the 5-FU-resistant cell line LoVo/5-Fu, and was inversely correlated with the extent of 5-FU chemoresistance. Cytotoxicity assay showed that the inhibition of miR-203 expression enhanced 5-FU chemoresistance in colorectal cancer cells, while miR-203 overexpression increased 5-FU chemosensitivity. We then validated that thymidylate synthase (TYMS) was a direct target of miR-203 and miR-203 suppressed TYMS protein levels. Silencing of TYMS enhanced 5-FU chemosensitivity, similar to the roles of miR-203. Finally, we discovered that miR-203 increased the inhibitory effects of 5-FU on tumor growth in vivo. Overall, our data indicate that miR-203 enhances 5-FU chemosensitivity via the downregulation of TYMS in colorectal cancer and provide important insight into the mechanism of 5-FU resistance in colorectal cancer patients. More important, the present study suggests that miR-203 has the potential as a therapeutic strategy for 5-FU-resistant colorectal cancer.
authors.affiliation: Colorectal Center, Tianjin Union Medical Center, Tianjin 300121, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of General Surgery, Qingdao Hiser Medical Center, Qingdao, Shandong 266033, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Colorectal Center, Tianjin Union Medical Center, Tianjin 300121, P.R. China.
authors.forename: Xi-Peng
authors.initials: XP
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage* / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; C000600377:TYMS protein, human; D013940:Thymidylate Synthase; D005472:Fluorouracil