Original articles
Lu Chen, Le Chen, Zhiyuan Qin, Jinxiu Lei, Sheng Ye, Kui Zeng, Hua Wang, Meidan Ying, Jianqing Gao, Su Zeng, Lushan Yu. Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 1008-1020

Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2
Lu Chena, Le Chena, Zhiyuan Qina, Jinxiu Leia, Sheng Yeb, Kui Zenga, Hua Wangc, Meidan Yinga, Jianqing Gaoa, Su Zenga, Lushan Yua
a Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;
b Paediatric Intensive Care Unit, the Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;
c Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou 310022, China
Renal cell carcinoma (RCC) is one of the most common malignant tumors affecting the urogenital system, accounting for 90% of renal malignancies. Traditional chemotherapy options are often the front-line choice of regimen in the treatment of patients with RCC, but responses may be modest or limited due to resistance of the tumor to anticarcinogen. Downregulated expression of organic cation transporter OCT2 is a possible mechanism underlying oxaliplatin resistance in RCC treatment. In this study, we observed that miR-489-3p and miR-630 suppress OCT2 expression by directly binding to the OCT2 3'-UTR. Meanwhile, via 786-O-OCT2-miRNAs stable expression cell models, we found that miRNAs could repress the classic substrate 1-methyl-4-phenylpyridinium (MPP+), fluorogenic substrate N,N-dimethyl-4-(2-pyridin-4-ylethenyl) aniline (ASP+), and oxaliplatin uptake by OCT2 both in vitro and in xenografts. In 33 clinical samples, miR-489-3p and miR-630 were significantly upregulated in RCC, negatively correlating with the OCT2 expression level compared to that in adjacent normal tissues, using tissue microarray analysis and qPCR validation. The increased binding of c-Myc to the promoter of pri-miR-630, responsible for the upregulation of miR-630 in RCC, was further evidenced by chromatin immunoprecipitation and dual-luciferase reporter assay. Overall, this study indicated that miR-489-3p and miR-630 function as oncotherapy-obstructing microRNAs by directly targeting OCT2 in RCC.
Key words:    OCT2    miRNA    Renal cell carcinoma    Epigenetic regulation    Oxaliplatin   
Received: 2018-08-25     Revised: 2018-11-04
DOI: 10.1016/j.apsb.2019.01.002
Funds: This work was supported by grants from National Natural Science Foundation of China (81773817), The National Key Research and Development Program of China (2017YFC0908600), Fundamental Research Funds for the Central Universities (2017XZZX011-04, China) and Zhejiang University K.P.Chao's High Technology Development Foundation (China).
Corresponding author: Lushan Yu     Email:yuls@zju.edu.cn
Author description:
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Lu Chen
Le Chen
Zhiyuan Qin
Jinxiu Lei
Sheng Ye
Kui Zeng
Hua Wang
Meidan Ying
Jianqing Gao
Su Zeng
Lushan Yu

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