Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Ubiquitin‑specific protease12 (USP12) is specifically upregulated in the tumor tissues of patients with HCC compared with the corresponding adjacent normal tissues. However, the relationship between USP12 and the growth of HCCs is not fully understood. In the present study, USP12 was knocked down in HCCcell lines to investigate its effects on proliferation and apoptosis. The results showed that USP12‑knockdown could inhibit the proliferation and promote apoptosis in HCCcell lines. Flow cytometry analysis also showed that USP12 could induce cell cycle arrest at the G2/Mstage. Invivo experiments showed that USP12‑knockdown could suppress tumor growth in mice, and immuno‑blotting revealed that USP12 could induce G2/M arrest through the cyclin dependent kinase1/cyclinB1 axis, and trigger apoptosis via the p38/mitogen‑activated protein kinase pathway. These data strongly indicate that USP12 is a potential target for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults [1]
The results indicated that Ubiquitin‐specific protease 12 (USP12)‐knockdown resulted in a reduced proportion of cells in the G0/G1 phase and an increased proportion in the G2/M phase, and that apoptosis was increased after USP12‐knockdown (Fig. 4A and D)
The levels of cleaved‐caspase 9 and cleaved‐caspase 3 were upregulated after USP12‐knockdown, while caspase 9 and caspase 3 were not changed after USP12‐knockdown. (B) The level of cyclin B1, Cdk1 and Cdc25c was decreased after USP12‐knockdown
Summary
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults [1]. Alcoholism, obesity and diabetes are the major risk factors of HCC [4], which result in chronic inflammation, Key words: ubiquitin specific protease 12, hepatocellular carcinoma, p38/mitogen‐activated protein kinase pathway leading to the destruction and regeneration of hepatocytes, as well as genetic mutations and dysregulation of growth signals [5,6]. The ubiquitin proteasome system (UPS) plays an important role in biological processes, especially in tumor cells [8], and ~95 putative deubiquitinating enzymes have been identified in humans [9]. As the reverse process of ubiquitination, deubiquitination serves an important role [10,11]
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