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The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) represents the second cause of cancer-related mortality worldwide and is associated with poor prognosis, especially in patients not amenable for curative treatments. The multi-kinase inhibitor sorafenib represents the first-line treatment option for advanced HCC; nevertheless, its effectiveness is limited due to tumor heterogeneity as well as innate or acquired drug resistance, raising the need for new therapeutic strategies. MicroRNAs (miRNAs) involvement in treatment response as well as their safety and efficacy in preclinical models and clinical trials have been widely documented in the oncologic field, including HCC. Here, we identified miR-494 upregulation in a subgroup of human and rat HCCs with stem cell-like characteristics, as well as multiple epigenetic mechanisms involved in its aberrant expression in HCC cell lines and patients. Moreover, we identified p27, puma and pten among miR-494 targets, contributing to speed up cell cycle progression, enhance survival potential in stressful conditions and increase invasive and clonogenic capabilities. MiR-494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines and, in line, high miR-494 levels associated with decreased sorafenib response in two HCC animal models. A sorafenib-combined anti-miR-494-based strategy revealed an enhanced anti-tumor potential with respect to sorafenib-only treatment in our HCC rat model. In conclusion, our findings suggested miR-494 as a possible therapeutic target as well as a candidate biomarker for patient stratification in advanced HCC.

SUBMITTER: Pollutri D

PROVIDER: S-EPMC5849044 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma.

Pollutri Daniela D Patrizi Clarissa C Marinelli Sara S Giovannini Catia C Trombetta Elena E Giannone Ferdinando A FA Baldassarre Maurizio M Quarta Santina S Vandewynckel Y P YP Vandierendonck A A Van Vlierberghe H H Porretti Laura L Negrini Massimo M Bolondi Luigi L Gramantieri Laura L Fornari Francesca F

Cell death & disease 20180105 1

Hepatocellular carcinoma (HCC) represents the second cause of cancer-related mortality worldwide and is associated with poor prognosis, especially in patients not amenable for curative treatments. The multi-kinase inhibitor sorafenib represents the first-line treatment option for advanced HCC; nevertheless, its effectiveness is limited due to tumor heterogeneity as well as innate or acquired drug resistance, raising the need for new therapeutic strategies. MicroRNAs (miRNAs) involvement in treat ...[more]

PMID: 29305580

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Project description:BackgroundHepatocellular carcinoma (HCC) is a challenging malignancy of global importance, it is the third most common cause of cancer-related mortality worldwide. In the last years the multikinase inhibitor sorafenib has been used for advanced HCC, but some patients do not benefit from this therapy; thus, novel therapeutic options based on molecular approaches are urgently needed. microRNAs are short non coding RNAs involved in several physiological and pathological conditions including HCC and increasing evidence describes miRs as good tools for the molecular targeted therapies in HCC. The purpose of this study was to identify novel approaches to sensitize the HCC cells to sorafenib by microRNAs targeting urokinase-type plasminogen activator (uPA).MethodsThe miR-193a was validated as negative regulator of urokinase-type plasminogen activator (uPA) in 2 HCC undifferentiated cell lines by transient transfection of miR and anti-miR molecules. The molecular interaction between miR-193a and uPA mRNA target was verified by luciferase reporter assay. The miR-193a expression level was evaluated by stem-loop real time PCR in tumoral tissues from 39 HCC patients. The HCC cells were co-treated with sorafenib and miR-193a and the effects on cellular proliferation, apoptosis were tested. The effect of sorafenib on c-met expression levels was assessed by western blotting.ResultsThe miR-193a has resulted a negative regulator of uPA in both the HCC cell lines tested. The miR-193a expression has resulted dysregulated in tumoral tissues from 39 HCC patients. We found miR-193a down-regulation in HCC respect to peritumoral (PT) tissues and more in the cirrhotic HCCs than in non-cirrhotic ones. Transfection of HA22T/VGH HCC cells with miR-193a decreased proliferation and increased apoptosis, and combined treatment with miR-193a and sorafenib led to further proliferation inhibition.ConclusionsOur results present new advances in the post-transcriptional miR-mediated mechanisms of uPA and they suggest a new strategy to impair the aggressive behavior of HCC cells. Our findings could be helpful to explore novel approaches for multi-target and multi-agent therapies of the HCC.

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

The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma.

Publications

The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma.

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