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MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression.

ABSTRACT: We investigated MAPK14-dependent resistance to sorafenib in hepatocellular carcinoma (HCC). Bioinformatics analysis and dual luciferase reporter assays in HCC cell lines showed that miR-216a-3p directly binds to the 3'UTR of MAPK14 mRNA and downregulates MAPK14 protein expression. Consequently, miR-216a-3p expression correlates inversely with MAPK14 protein levels in HCC patient tissues. miR-216a-3p overexpression significantly increases the sorafenib sensitivity of HCC cells by suppressing MAPK14 expression and reducing the subsequent activation of the MEK/ERK and ATF2 signaling pathways. The growth of xenograft tumors derived from miR-216a-3p-overexpression HCC cells was significantly diminished in sorafenib-treated Balb/c nude mice compared to controls. High miR-216a-3p levels in HCC tissue samples prior to treatment correlated with a better sorafenib response and favorable prognosis. Our findings thus demonstrate that miR-216a-3p enhances sorafenib sensitivity in HCC cells and tumor tissues by decreasing MAPK14 levels, thereby inhibiting the MAPK14-dependent MEK/ERK and ATF2 signaling.

SUBMITTER: Wan Z

PROVIDER: S-EPMC7585128 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression.

Wan Zhong Z Liu Tingyu T Wang Liang L Wang Rong R Zhang Hai H

Aging 20200921 18

We investigated MAPK14-dependent resistance to sorafenib in hepatocellular carcinoma (HCC). Bioinformatics analysis and dual luciferase reporter assays in HCC cell lines showed that miR-216a-3p directly binds to the 3'UTR of MAPK14 mRNA and downregulates MAPK14 protein expression. Consequently, miR-216a-3p expression correlates inversely with MAPK14 protein levels in HCC patient tissues. miR-216a-3p overexpression significantly increases the sorafenib sensitivity of HCC cells by suppressing MAPK ...[more]

PMID: 33021963

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Project description:BackgroundSorafenib can prolong the survival of patients with advanced hepatocellular carcinoma (HCC). However, drug resistance remains the main obstacle to improving its efficiency. This study aimed to explore the likely molecular mechanism of sorafenib resistance.MethodsDifferentially expressed microRNAs (miRNAs) related to sorafenib response were analyzed with the Limma package in R software. The expression levels of miR-126-3p and sprouty-related EVH1 domain-containing protein 1 (SPRED1) in HCC cells were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and proliferation were detected with Cell Counting Kit-8 (CCK-8), EdU proliferation, and clone formation assays. Transwell assays were performed to measure cell migration and invasion. TargetScan, MicroRNA Target Prediction Database (miRDB), and StarBase v2.0 were used to predict the targets of miR-126-3p. SPRED1 was confirmed as a target gene of miR-126-3p by dual-luciferase reporter assay and Western blotting. Finally, the in vivo anti-tumor effect of LV-miR-126-3p inhibitor combined with sorafenib was evaluated via subcutaneous tumor models.ResultsHCC cells with high expression of miR-126-3p exhibited increased resistance to sorafenib. The results of bioinformatics analysis and the dual-luciferase reporter assay showed that miR-126-3p directly targeted SPRED1. The sensitivity of HCC cells to sorafenib was markedly enhanced by SPRED1 upregulation. Gain- and loss-of function experiments verified that miR-126-3p induced sorafenib resistance in HCC through downregulating SPRED1. Furthermore, the inhibition of miR-126-3p markedly increased the effectiveness of sorafenib against HCC in vivo. Mechanistically, our results suggested that miR-126-3p promoted sorafenib resistance via targeting SPRED1 and activating the ERK signaling pathway.ConclusionsOur study demonstrates that regulating the miR-126-3p/SPRED1 axis might be a promising strategy for enhancing the antitumor effect of sorafenib in the treatment of HCC.

Dataset Information

MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression.

Publications

MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression.

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