Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2
Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2
复制标题
miR-489-3p 和 miR-630 的上调通过靶向 OCT2 抑制肾细胞癌中奥沙利铂的摄取
DOI：
10.1016/j.apsb.2019.01.002
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发表时间：
2019-09-01
影响因子：
14.5
通讯作者：
Yu, Lushan
中科院分区：
文献类型：
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作者：
Chen, Lu;Chen, Le;Yu, Lushan
肾细胞癌是泌尿生殖系统最常见的恶性肿瘤之一，占肾脏恶性肿瘤的90%。传统的化疗方案通常是治疗RCC患者的一线方案选择，但由于肿瘤对抗癌药的耐药性，反应可能是温和或有限的。有机阳离子转运蛋白OCT 2表达下调是肾细胞癌奥沙利铂耐药的可能机制。在这项研究中，我们观察到miR-489- 3 p和miR-630通过直接结合OCT 2 3 '-UTR来抑制OCT 2表达。同时，通过786-O-OCT 2-miRNAs稳定表达细胞模型，我们发现miRNAs在体外和异种移植中均能抑制OCT 2对经典底物1-甲基-4-苯基吡啶（MPP+）、荧光底物N，N-二甲基-4-（2-吡啶-4-基乙烯基）苯胺（ASP（+））和奥沙利铂的摄取。在33例临床标本中，采用组织微阵列分析和qPCR验证，与癌旁正常组织相比，miR-489- 3 p和miR-630在RCC中显著上调，与OCT 2表达水平呈负相关。通过染色质免疫沉淀和双荧光素酶报告基因分析，进一步证明了c-Myc与pri-miR-630启动子的结合增加，导致RCC中miR-630的上调。总体而言，这项研究表明，miR-489- 3 p和miR-630通过直接靶向RCC中的OCT 2作为肿瘤治疗阻断microRNA发挥作用。(C)2019中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
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. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.