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CircFOXM1 contributes to sorafenib resistance of hepatocellular carcinoma cells by regulating MECP2 via miR-1324.

ABSTRACT: As one of the most common malignant tumors, hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths around the world. Emerging studies have indicated that circular RNAs (circRNAs), which play a crucial role in HCC pathogenesis and metastasis, are differentially expressed in HCC. However, the regulatory mechanisms of circRNA on sorafenib resistance of HCC are still unknown. In our study, we identified a novel circRNA, circFOXM1, using RNA sequencing (RNA-seq) that was increased in sorafenib-resistant HCC tissues. Functionally, circFOXM1 significantly inhibited HCC growth and enhanced sorafenib toxicity in vitro. Mechanistically, circFOXM1 acted as a sponge of microRNA (miR)-1324, which is a negative regulator of MECP2, indicating that circFOXM1 downregulation would regulate sorafenib resistance of HCC via releasing more free miR-1324 and suppressing MECP2 expression. Furthermore, miR-1324 overexpression was capable of reversing the circFOXM1-induced malignant phenotypes and elevated expression of MECP2 in HCC cells. circFOXM1 partially contributed to sorafenib resistance of HCC cells through upregulating MECP2 expression by sponging miR-1324.

SUBMITTER: Weng H

PROVIDER: S-EPMC7868711 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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circFOXM1 contributes to sorafenib resistance of hepatocellular carcinoma cells by regulating MECP2 via miR-1324.

Weng Hanqin H Zeng Lexiang L Cao Linhui L Chen Tao T Li Yanshan Y Xu Yunxiuxiu Y Peng Yaorong Y Ye Yibiao Y

Molecular therapy. Nucleic acids 20210101

As one of the most common malignant tumors, hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths around the world. Emerging studies have indicated that circular RNAs (circRNAs), which play a crucial role in HCC pathogenesis and metastasis, are differentially expressed in HCC. However, the regulatory mechanisms of circRNA on sorafenib resistance of HCC are still unknown. In our study, we identified a novel circRNA, circFOXM1, using RNA sequencing (RNA-seq) that was increased ...[more]

PMID: 33614231

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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.

Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted.MethodsWe analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice.ResultsHypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the cholesterol sensor SCAP and consequent deposition of cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo.ConclusionsSCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC.

Dataset Information

CircFOXM1 contributes to sorafenib resistance of hepatocellular carcinoma cells by regulating MECP2 via miR-1324.

Publications

circFOXM1 contributes to sorafenib resistance of hepatocellular carcinoma cells by regulating MECP2 via miR-1324.

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