- 作者: Tong-tong Li, Jie Mou, Yao-jie Pan, Fu-chun Huo, Wen-qi Du, Jia Liang, Yang Wang, Lan-sheng Zhang and Dong-sheng Pei
- 作者服務機構: 1. Department of Pathology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, People’s Republic of China 2. Department of Pathology and Pathophysiology, Jiangsu Vocational College of Medicine, Yancheng, 224005, Jiangsu, China 3. Jiangsu Key Laboratory of New Drug and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221006, China 4. Department of Oncological Radiotherapy, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- 中文摘要:
- 英文摘要:
Background
Sorafenib 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.
Methods
In 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.
Results
We 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.
Conclusions
PAK5 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. - 中文關鍵字:
- 英文關鍵字: Hepatocellular carcinoma, Sorafenib, MiR-138-1-3p, p21-Activated kinases 5, Wnt/β-catenin pathway, ABCB1