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08 April 2018 : Laboratory Research  

Upregulation of Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Mediates the Reversal Effect of Verapamil on Chemo-Resistance to Adriamycin of Hepatocellular Carcinoma

Guangshan Yang123ABCDEF, Gaofei Fan2BCDE, Tengyue Zhang2ABCDEF, Kelong Ma4ABCD, Jin Huang2BC, Miao Liu2AB, Xiaolu Teng2AB, Kun Xu2AB, Pingsheng Fan12ACDFG, Dongmiao Cheng5ACDFG

DOI: 10.12659/MSM.908925

Med Sci Monit 2018; 24: LBR2072-2082

Abstract

BACKGROUND: The aim of this study was to investigate the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in the reversal effect of verapamil (VER) on chemo-resistance to Adriamycin (ADM) in treatment of hepatocellular carcinoma (HCC).

MATERIAL AND METHODS: HCC cell lines SMMC-7721 and BEL-7402 were used as model cell lines. High-throughput transcriptome sequencing based on Illumina technology was used to screen whether UCHL1 mediated the reversal effect of VER on chemo-resistance. Quantitative real-time PCR (qRT-PCR) was performed to determine the expression level of UCHL1 mRNA in HCC cells, and western blot analysis was performed to examine the protein expression of UCHL1 protein in HCC cells. Immunohistochemistry assay was performed to determine the protein expression of UCHL1 in tissue samples from patients presenting with either positive or negative responses to the reversal therapeutic regimen of VER. Moreover, cell models with UCHL1 knockdown and overexpression were established to examine the reversal effect of VER on chemo-resistance to ADM in HCC cells. Cell apoptosis was determined by flow cytometry following Annexin V-PI staining.

RESULTS: The expression levels of UCHL1 genes correlated with the level of apoptosis induced by ADM+VER. Overexpression of UCHL1 genes promoted apoptosis in cells treated with VER+ADM. UCHL1 knockdown using siRNA weakened the effect of ADM+VER, indicating that ADM+VER promotes HCC cell apoptosis and that UCHL1 genes participate in VER-mediated promotion in tumor cell apoptosis.

CONCLUSIONS: Upregulation of UCHL1 enhanced the reversal effect of VER on chemo-resistance to ADM and promoted cell apoptosis. The underlying mechanism of the function of UCHL1 and the signaling pathway involved in its effect are to be investigated in our future research.

Keywords: Antineoplastic Combined Chemotherapy Protocols, Drug Resistance, Epirubicin, Ubiquitin Thiolesterase, Verapamil

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750