Upregulation of USP22 and ABCC1 during Sorafenib Treatment of Hepatocellular Carcinoma Contribute to Development of Resistance

Cells

Yen-Ying Chen¹  Chien-Wei Su²  Jaw-Ching Wu³  Yung-Sheng Chang³  San-Chi Chen³  Yuh-Jin Liang⁴ 

[1] Department of Pathology, Taipei Veterans General Hospital, Taipei 11217, Taiwan;Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;Medical Research Department, Taipei Veterans General Hospital, Taipei 11217, Taiwan;

关键词: sorafenib resistance;    USP22;    ABCC1;    hepatocellular carcinoma;   

DOI  :  10.3390/cells11040634

来源: DOAJ

【 摘 要 】

Sorafenib is a small molecule that blocks tumor proliferation by targeting the activity of multi-kinases for the treatment of advanced hepatocellular carcinoma (HCC). Increasing sorafenib resistance following long-term treatment is frequently encountered. Mechanisms underlying sorafenib resistance remain not completely clear. To further understand the mechanism of sorafenib resistance in HCC, we established sorafenib-resistant cell lines by slowly increasing sorafenib concentration in cell culture medium. Upregulation of USP22 and ABCC1 were found in Sorafenib-resistant cells. Sorafenib-resistant cells treated with USP22 siRNA showed significant reduction in endogenous mRNA and protein levels of ABCC1. During sorafenib treatment, upregulation of USP22 increases ABCC1 expression and subsequently contributes to sorafenib resistance in HCC cells. Immunohistochemical analysis revealed a positive correlation between USP22 and ABCC1 expression in tissue samples from sorafenib-resistant patients (Pearson’s correlation = 0.59, p = 0.03). Our findings indicate that upregulation of USP22 and ABCC1 expression during treatment contribute to sorafenib resistance in HCC cells and that USP22 has strong potential as a therapeutic target for overcoming sorafenib resistance in HCC patients.

【 授权许可】

Unknown