title: miR-340 reverses cisplatin resistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway.
abstract: Many chemotherapeutic agents have been successfully used to treat hepatocellular carcinoma (HCC); however, the development of chemoresistance in liver cancer cells usually results in a relapse and worsening of prognosis. It has been demonstrated that DNA methylation and histone modification play crucial roles in chemotherapy resistance. Currently, extensive research has shown that there is another potential mechanism of gene expression control, which is mediated through the function of short noncoding RNAs, especially for microRNAs (miRNAs), but little is known about their roles in cancer cell drug resistance. In present study, by taking advantage of miRNA effects on the resistance of human hepatocellular carcinoma cells line to cisplatin, it has been demonstrated that miR-340 were significantly downregulated whereas Nrf2 was upregulated in HepG2/ CDDP (cisplatin) cells, compared with parental HepG2 cells. Bioinformatics analysis and luciferase assays of Nrf2-3'-untranslated region-based reporter constructor indicated that Nrf2 was the direct target gene of miR- 340, miR-340 mimics suppressing Nrf2-dependent antioxidant pathway and enhancing the sensitivity of HepG2/ CDDP cells to cisplatin. Interestingly, transfection with miR-340 mimics combined with miR-340 inhibitors reactivated the Nrf2 related pathway and restored the resistance of HepG2/CDDP cells to CDDP. Collectively, the results first suggested that lower expression of miR-340 is involved in the development of CDDP resistance in hepatocellular carcinoma cell line, at least partly due to regulating Nrf2-dependent antioxidant pathway.
authors.affiliation: Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China E-mail : zhengfang@whu.edu.cn, linxy1968@126.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Chen
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Wu
authors.forename: Jian-Jian
authors.initials: JJ
authors.lastname: Zheng
authors.forename: Jian-Rong
authors.initials: JR
authors.lastname: Yang
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Chen
authors.forename: Zeng-Qiang
authors.initials: ZQ
authors.lastname: Chen
authors.forename: Cun-Li
authors.initials: CL
authors.lastname: Liu
authors.forename: Sheng-Ying
authors.initials: SY
authors.lastname: Chi
authors.forename: Jia-Ying
authors.initials: JY
authors.lastname: Zheng
authors.forename: Hai-Xia
authors.initials: HX
authors.lastname: Huang
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Lin
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002945:Cisplatin; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C570046:MIRN340 microRNA, human; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D002945:Cisplatin