Background Ubiquilin-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. Methods Immunochemistry, 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. Results Ubiquilin-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. Conclusion The 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.

中文翻译：

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UBQLN4 通过激活 wnt-β-catenin 通路促进 HCC 的进展，并受 miR-370 的调节。

背景泛素-4 (UBQLN4) 是泛素-蛋白酶体系统的成员，通常在许多肿瘤细胞中上调。它的过度表达与各种癌症疾病的不良疾病结果有关。然而，UBQLN4 在肝细胞癌 (HCC) 发展中的潜在机制尚未阐明。方法采用免疫化学、实时荧光定量PCR和western blotting检测UBQLN4在癌组织中的表达水平。进行单变量、Cox 回归和 Kaplan-Meier 分析以确定 UBQLN4 表达与 HCC 预后之间的关联。进行细胞计数 Kit-8 (CCK-8)、transwell、EDU 和集落形成测定以评估 UBQLN4 在 HCC 细胞进展中的作用。通过基因集富集分析和荧光素酶报告基因实验，寻找UBQLN4在HCC中的作用机制。结果 Ubiquilin-4 (UBQLN4) 在 HCC 组织中过度表达。此外，UBQLN4的过表达与HCC患者较差的总生存期和无病生存率相关。功能丧失分析表明，UBQLN4 的抑制在体内和体外抑制了 HCC 细胞的增殖和侵袭。KEGG（京都基因和基因组百科全书）分析表明，UBQLN4可以调节HCC细胞中wnt-β-catenin通路的激活。此外，我们的结果显示 UBQLN4 被 miR-370 下调，miR-370 在 HCC 进展中充当肿瘤抑制基因。结论 本研究结果提示 miR-370/UBQLN4 轴可能在 HCC 的进展中起关键作用。这些发现可能为未来开发针对 HCC 的治疗药物的策略提供信息。