Open AccessUSP22 mediates the multidrug resistance of hepatocellular carcinoma via the SIRT1/AKT/MRP1 signaling pathway
Author(s) -
Ling Sunbin,
Li Jie,
Shan Qiaonan,
Dai Haojiang,
Lu Di,
Wen Xue,
Song Penghong,
Xie Haiyang,
Zhou Lin,
Liu Jimin,
Xu Xiao,
Zheng Shusen
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12067
Subject(s) - downregulation and upregulation , biology , protein kinase b , cancer research , multiple drug resistance , pi3k/akt/mtor pathway , ly294002 , abcc1 , cell growth , signal transduction , drug resistance , microbiology and biotechnology , biochemistry , atp binding cassette transporter , gene , transporter
Drug treatments for hepatocellular carcinoma ( HCC ) often fail because of multidrug resistance ( MDR ). The mechanisms of MDR are complex but cancer stem cells ( CSC s), which are able to self‐renew and differentiate, have recently been shown to be involved. The deubiquitinating enzyme ubiquitin‐specific protease 22 ( USP 22) is a marker for CSC s. This study aimed to elucidate the role of USP 22 in MDR of HCC and the underlying mechanisms. Using in vitro and in vivo assays, we found that modified USP 22 levels were responsible for the altered drug‐resistant phenotype of BEL 7402 and BEL / FU cells. Downregulation of USP 22 dramatically inhibited the expression of ABCC 1 (encoding MRP 1) but weakly influenced ABCB 1 (encoding P‐glycoprotein). Sirtuin 1 ( SIRT 1) was reported previously as a functional mediator of USP 22 that could promote HCC cell proliferation and enhance resistance to chemotherapy. In this study, USP 22 directly interacted with SIRT 1 and positively regulated SIRT 1 protein expression. Regulation of the expression of both USP 22 and SIRT 1 markedly affected the AKT pathway and MRP 1 expression. Inhibition of the AKT pathway by its specific inhibitor LY 294002 resulted in downregulation of MRP 1. USP 22 and MRP 1 expression was detected in 168 clinical HCC samples by immunohistochemical staining, and a firm relationship between USP 22 and MRP 1 was identified. Together, these results indicate that USP 22 could promote the MDR in HCC cells by activating the SIRT 1/ AKT / MRP 1 pathway. USP 22 might be a potential target, through which the MDR of HCC in clinical setting could be reversed.