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MiR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression.

ABSTRACT: Sorafenib, a multi-kinase inhibitor, is the only standard clinical drug for patients with advanced hepatocellular carcinoma (HCC); however, development of sorafenib resistance in HCC often prevents its long-term efficacy. Therefore, novel targets and strategies are urgently needed to improve the antitumor effect of sorafenib. In the present study, we examined the novel mechanisms of sorafenib resistance of HCC cells by investigating the difference in sorafenib sensitivity between two HCC cell lines. Sorafenib induced more apoptosis of HepG2 cells compared to Hep3B cells. Sorafenib exposure to HepG2 cells but not Hep3B cells increased the expression of proapoptotic factor PUMA, and activated PARP and caspase-3. Notably, microRNA-181a (miR-181a) expression levels were lower in HepG2 cells than in Hep3B cells. Exogenous miR-181a expression in HepG2 cells reduced apoptosis, whereas inhibition of miR-181a in Hpe3B cells increased apoptosis. In addition, we demonstrated that miR-181a directly targets RASSF1, a MAPK signaling factor, and knockdown of RASSF1 increased sorafenib resistance. Taken together, these results suggest that miR-181a provokes sorafenib resistance through suppression of RASSF1. Our data provide important insight into the novel therapeutic strategy against sorafenib resistance of HCC cells by targeting of miR-181a pathway.

SUBMITTER: Azumi J

PROVIDER: S-EPMC5021022 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression.

Azumi Junya J Tsubota Toshiaki T Sakabe Tomohiko T Shiota Goshi G

Cancer science 20160902 9

Sorafenib, a multi-kinase inhibitor, is the only standard clinical drug for patients with advanced hepatocellular carcinoma (HCC); however, development of sorafenib resistance in HCC often prevents its long-term efficacy. Therefore, novel targets and strategies are urgently needed to improve the antitumor effect of sorafenib. In the present study, we examined the novel mechanisms of sorafenib resistance of HCC cells by investigating the difference in sorafenib sensitivity between two HCC cell li ...[more]

PMID: 27384977

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Project description:BackgroundMetabolic reprogramming is a well-known marker of cancer, and it represents an early event during hepatocellular carcinoma (HCC) development. The recent approval of several molecular targeted agents has revolutionized the management of advanced HCC patients. Nevertheless, the lack of circulating biomarkers still affects patient stratification to tailored treatments. In this context, there is an urgent need for biomarkers to aid treatment choice and for novel and more effective therapeutic combinations to avoid the development of drug-resistant phenotypes. This study aims to prove the involvement of miR-494 in metabolic reprogramming of HCC, to identify novel miRNA-based therapeutic combinations and to evaluate miR-494 potential as a circulating biomarker.MethodsBioinformatics analysis identified miR-494 metabolic targets. QPCR analysis of glucose 6-phosphatase catalytic subunit (G6pc) was performed in HCC patients and preclinical models. Functional analysis and metabolic assays assessed G6pc targeting and miR-494 involvement in metabolic changes, mitochondrial dysfunction, and ROS production in HCC cells. Live-imaging analysis evaluated the effects of miR-494/G6pc axis in cell growth of HCC cells under stressful conditions. Circulating miR-494 levels were assayed in sorafenib-treated HCC patients and DEN-HCC rats.ResultsMiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions. High miR-494 serum levels associated with sorafenib resistance in preclinical models and in a preliminary cohort of HCC patients. An enhanced anticancer effect was observed for treatment combinations between antagomiR-494 and sorafenib or 2-deoxy-glucose in HCC cells.ConclusionsMiR-494/G6pc axis is critical for the metabolic rewiring of cancer cells and associates with poor prognosis. MiR-494 deserves attention as a candidate biomarker of likelihood of response to sorafenib to be tested in future validation studies. MiR-494 represents a promising therapeutic target for combination strategies with sorafenib or metabolic interference molecules for the treatment of HCC patients who are ineligible for immunotherapy.

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.

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MiR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression.

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miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression.

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