Abstract
BackgroundUbiquilin-4 (UBQLN4) is a member of the ubiquitin–proteasome system that is usually upregulated in many tumor cells. Its overexpression has been associated with poor disease outcomes in various cancer diseases. However, the underlying mechanism of UBQLN4 in the development of hepatocellular carcinoma (HCC) has not been elucidated.MethodsImmunochemistry, real-time PCR, and western blotting were used to evaluate the expression levels of UBQLN4 in cancer tissues. Univariate, Cox-regression, and Kaplan–Meier analyses were performed to determine the association between UBQLN4 expression and HCC prognosis. Cell Counting Kit-8 (CCK-8), transwell, EDU and colony formation assays were conducted to evaluate the role of UBQLN4 in HCC cell progression. The gene set enrichment analysis and luciferase reporter experiments were conducted to find the mechanism of UBQLN4 in HCC.ResultsUbiquilin-4 (UBQLN4) was overexpressed in HCC tissues. Besides, overexpression of UBQLN4 was associated with poor overall survival and disease-free survival rate of HCC patients. The loss-of-function analysis revealed that suppression of UBQLN4 inhibited the proliferation and invasion of HCC cells in vivo and in vitro. The KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that UBQLN4 could regulate activation of the wnt-β-catenin pathway in HCC cells. Furthermore, our results showed that UBQLN4 was downregulated by miR-370, which acted as a tumor suppressor gene in HCC progression.ConclusionThe results of the present study suggest that the miR-370/UBQLN4 axis may play a critical role in the progression of HCC. These findings may inform future strategies for the development of therapeutic agents against HCC.
Highlights
Ubiquilin-4 (UBQLN4) is a member of the ubiquitin–proteasome system that is usually upregulated in many tumor cells
Overexpression of UBQLN4 is correlated with poor prognosis of Hepatocellular carcinoma (HCC) patients To investigate the role of UBQLN4 in HCC progression, TCGA and GEO database analysis were performed to determine the variation in UBQLN4 mRNA levels between HCC and normal tissues
These results showed that UBQLN4 is upregulated in HCC tissues and its expression is correlated with poor prognosis of HCC patients
Summary
Ubiquilin-4 (UBQLN4) is a member of the ubiquitin–proteasome system that is usually upregulated in many tumor cells. The underlying mechanism of UBQLN4 in the development of hepatocellular carcinoma (HCC) has not been elucidated. Hepatocellular carcinoma (HCC) is one of the most common and highly malignant solid tumors, and is the thirdleading cause of cancer-related deaths worldwide [1, 2]. Many treatment options for HCC exist, including surgical resection, liver transplantation (LT), transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA) and molecular targeted therapy (sorafenib). These treatments can greatly improve the 5-year survival rate of HCC [3, 4]. Because of the heterogeneity and high invasiveness of HCC cells, recurrence and metastasis are still common. Finding molecular markers for recurrence and metastasis in HCC is necessary for the improvement of survival rates of patients.
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