Abstract
BackgroundSorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carcinoma (HCC) patients. However, the existence of sorafenib resistance has limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC.MethodsIn this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in sorafenib-resistant HCC cells and parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assays and flow cytometric analyses. The mechanisms for the involvement of PAK5 were examined via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib resistant characteristics were investigated by a xenotransplantation model.ResultsWe detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in sorafenib-resistance HCC cell lines. Mechanistic studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 enhanced the phosphorylation and nuclear translocation of β-catenin that increased the transcriptional activity of a multidrug resistance protein ABCB1.ConclusionsPAK5 contributed to the sorafenib resistant characteristics of HCC via β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated sorafenib resistance in HCC, which provided a potential therapeutic target in advanced HCC patients.
Highlights
Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carci‐ noma (HCC) patients
Results miR‐138‐1‐3p expression was reduced in sorafenib‐resistant cells and may participate in resistance development To explore the underlying mechanisms of sorafenib resistance in HCC, we introduced the sorafenib-resistant cell models via chronic exposure to sorafenib in HCC cell lines
We further tested the expression of miR-138-1-3p in tumor tissues and adjacent normal tissues from 40 HCC patients by Quantitative real-time PCR (qRT-PCR), and significant decrease of miR-138-1-3p was found in tumor tissue (Fig. 1E), indicating that miR138-1-3p is important in HCC development
Summary
Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carci‐ noma (HCC) patients. The existence of sorafenib resistance has limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC. Sorafenib is the Food and Drug Administration (FDA)approved first-line targeted drug for advantage HCC patients [2, 3]. Sorafenib inhibits tumor growth by targeting angiogenesis and tumorigenesis pathways [4]. Approximately 30% of patients can benefit from sorafenib due to acquired drug resistance [6]. Understanding the resistance mechanism(s) of sorafenib in HCC has pivotal significance
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