miR-203 enhances chemosensitivity to 5-fluorouracil by targeting thymidylate synthase in colorectal cancer

Li,Tao; Gao,Feng; Zhang,Xi-Peng

doi:10.3892/or.2014.3646

miR-203 enhances chemosensitivity to 5-fluorouracil by targeting thymidylate synthase in colorectal cancer

Authors:
- Tao Li
- Feng Gao
- Xi-Peng Zhang
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Affiliations: Colorectal Center, Tianjin Union Medical Center, Tianjin 300121, P.R. China, Department of General Surgery, Qingdao Hiser Medical Center, Qingdao, Shandong 266033, P.R. China
Published online on: December 4, 2014 https://doi.org/10.3892/or.2014.3646
Pages: 607-614

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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.

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