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RBMX contributes to hepatocellular carcinoma progression and sorafenib resistance by specifically binding and stabilizing BLACAT1.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the top five causes of cancer death. The interaction of RNA binding proteins and long no coding RNA play vital role in malignant tumor progression, and even contribute to chemoresistance. RNA binding protein X (RBMX) plays a vital role in binding and stabilizing many proteins. In this study, we have identified RBMX significantly contributes to the tumorigenesis and sorafenib resistance of hepatocellular carcinoma (HCC). We observed that RBMX was highly expressed in both the HCC patient tissues and HCC cell lines. The HCC cell's viability, proliferation, and sorafenib resistance ability were both increased when RBMX was overexpressed. Additional, RBMX also promotes HCC development and chemoresistance in vivo. Further, we found that the autophagy level was increased in HCC cells, which RBMX was up regulated, with sorafenib processing. Interestingly, our study found that long no coding RNA bladder cancer associated transcript 1 (LncBLACAT1) was also raised in HCC. Mechanically, RIP, RNA pull-down and RNA Stability assay proved that RBMX could specially binds BLACAT1's mRNA and matins its expression, which is high degree of consistency with catRAPI database prediction. This mechanism of action is beneficial for cancer cells proliferation, anti-apoptotic, and colony formation with sorafenib treatment. Further, the autophagy level and cancer cell stemness were also improved when RBMX/BLACAT1 upregulated. Our study indicated that hepatoma cells can improve their proliferation, colony ability and autophagy by RBMX stabilizing BLACAT1 expression then promote HCC development and drug resistance. Hence, RBMX could be considered as novel therapeutic target for HCC treatment strategies.

SUBMITTER: Song Y

PROVIDER: S-EPMC7716158 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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RBMX contributes to hepatocellular carcinoma progression and sorafenib resistance by specifically binding and stabilizing BLACAT1.

Song Yanan Y He Saifei S Ma Xing X Zhang Miao M Zhuang Juhua J Wang Guoyu G Ye Ying Y Xia Wei W

American journal of cancer research 20201101 11

Hepatocellular carcinoma (HCC) is one of the top five causes of cancer death. The interaction of RNA binding proteins and long no coding RNA play vital role in malignant tumor progression, and even contribute to chemoresistance. RNA binding protein X (RBMX) plays a vital role in binding and stabilizing many proteins. In this study, we have identified RBMX significantly contributes to the tumorigenesis and sorafenib resistance of hepatocellular carcinoma (HCC). We observed that RBMX was highly ex ...[more]

PMID: 33294259

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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.

Project description:Background Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), even though acquired resistance to sorafenib has been found in many HCC patients, resulting in poor prognosis. Accumulating evidence demonstrates that liver cancer stem cells (LCSCs) contribute to sorafenib resistance in HCC. The inflammatory factor interleukin 6 (IL-6) plays a role in sorafenib resistance in HCC. However, the mechanism by which IL-6 in LCSCs is involved in the process of HCC sorafenib resistance remains elusive. Methods In this study, the sorafenib-resistant cell line PLC/PRF/5-R was generated by the concentration gradient method, and cell viability was determined by the CCK-8 assay. LCSCs were isolated from the PLC/PRF/5-R cell line by flow cytometry, and tumorigenesis was confirmed in nude mice. Blockade of IL-6 cells was achieved by lentiviral-mediated interference. The protein levels of stem cell markers (EpCAM, CD44), stemness markers (Oct3/4, ?-catenin), and hepatocyte differentiation markers (glucose-6-phosphate, AFP) were measured by Western blotting analysis. Finally, a xenograft model was used to evaluate the function of IL-6 in the sorafenib resistance of HCC. Results The stable sorafenib-resistant HCC cell line PLC/PRF/5-R was established and showed significant epithelial–mesenchymal transition (EMT) characteristics; the isolated resistant LCSCs from PLC/PRF/5-R were more tumorigenic than the control LCSCs. We showed that IL-6, IL-6R, STAT3 and GP130 expression were dramatically increased in resistant LCSCs compared to control LCSCs. Downregulation of IL-6 expression with short hairpin RNA (shRNA) restored sorafenib sensitivity in resistant LCSCs, suggesting the critical roles of IL-6/STAT3 in inducing sorafenib resistance. Furthermore, a xenograft tumor model showed that IL-6 downregulation improved the antitumor effect of sorafenib. Conclusion LCSCs play an important role in sorafenib-resistant HCC, and inhibition of the IL-6/STAT3 signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo. These findings demonstrate that IL-6 in LCSCs may function as a novel target for combating sorafenib resistance in HCC.

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RBMX contributes to hepatocellular carcinoma progression and sorafenib resistance by specifically binding and stabilizing BLACAT1.

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RBMX contributes to hepatocellular carcinoma progression and sorafenib resistance by specifically binding and stabilizing BLACAT1.

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