FBXO42通过介导p57Kip2泛素化和降解促进肝细胞癌进展。

FBXO42 promotes hepatocellular carcinoma progression via mediating p57Kip2 ubiquitination and degradation.

作者信息

Zhou Bing, Wu Shasha, Hong Shengqian, Li Han, Jiang Zhi, Sun Yong, Qiu Jiannan, Qin Lei

机构信息

Department of General Surgery, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou, 215031, Jiangsu, China.

School of Medical Technology, Jiangsu College of Nursing, Huai'an, 223005, Jiangsu, China.

出版信息

Eur J Med Res. 2025 Aug 21;30(1):784. doi: 10.1186/s40001-025-03050-z.

DOI:10.1186/s40001-025-03050-z

PMID:40842039

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC), one of the most common malignancies, accounts for about 80% of all primary liver cancers. FBXO42 belongs to the F-box protein family and functions as a key component of the SCF (Skp1-Cullin-F-box) ubiquitin ligase complex, which is involved in the process of protein ubiquitination. The studies on the role of FBXO42 in different diseases are inadequate, especially in HCC.

METHODS

The expression and the clinical features of FBXO42 in HCC were assessed using the HCCDB, TCGA, and ICGC databases. cBioPortal and SangerBox databases were used to analyze the genetic alterations and mutation profile of FBXO42. TIMER, TISIDB and GEPIA databases were used to examine the correlation of FBXO42 with tumor-infiltrating immune cells, tumor-associated fibroblasts and cancer stemness. CCK8 assay, clone formation assay and EDU assay were utilized to reveal the cell viability and proliferation ability. Meanwhile, transwell assay was used to assess the cellular migration. UbiBrowser and Co-IP revealed the FBXO42-interacting protein in HCC. The hTFtarget, ENCODE and CHEA databases were used to predict potential transcriptional regulators.

RESULTS

Our data displayed that FBXO42 was highly expressed in HCC tissues and was associated with poor prognosis. Moreover, FBXO42 expression was correlated with immune cell infiltration and immune-related molecules, suggesting that FBXO42 may lead to a complex immune microenvironment in HCC. Meanwhile, our data revealed that the level of FBXO42 was positively associated with CAFs infiltration and cancer stemness. In addition, FBXO42 facilitated the malignant behaviors of HCC. Mechanistically, FBXO42 interacted p57Kip2, sequentially promoting p57Kip2 ubiquitination and degradation, ultimately leading to HCC progression. Finally, YY1 had been demonstrated to upregulate the expression of FBXO42 via transcriptional regulation.

CONCLUSIONS

This study revealed that FBXO42 promotes the malignancy of HCC through FBXO42-mediated p57Kip2 ubiquitination and degradation. Our findings underscore the possibility of FBXO42 as a potential therapeutic target for HCC.

摘要

背景

肝细胞癌（HCC）是最常见的恶性肿瘤之一，约占所有原发性肝癌的80%。FBXO42属于F-box蛋白家族，作为SCF（Skp1-Cullin-F-box）泛素连接酶复合体的关键组成部分发挥作用，该复合体参与蛋白质泛素化过程。关于FBXO42在不同疾病中的作用研究不足，尤其是在HCC中。

方法

使用HCCDB、TCGA和ICGC数据库评估FBXO42在HCC中的表达及临床特征。利用cBioPortal和SangerBox数据库分析FBXO42的基因改变和突变谱。使用TIMER、TISIDB和GEPIA数据库研究FBXO42与肿瘤浸润免疫细胞、肿瘤相关成纤维细胞和癌症干性的相关性。采用CCK8检测、克隆形成检测和EDU检测来揭示细胞活力和增殖能力。同时，使用Transwell检测评估细胞迁移。UbiBrowser和免疫共沉淀揭示了HCC中与FBXO42相互作用的蛋白。使用hTFtarget、ENCODE和CHEA数据库预测潜在的转录调节因子。

结果

我们的数据显示FBXO42在HCC组织中高表达，且与预后不良相关。此外，FBXO42表达与免疫细胞浸润和免疫相关分子相关，表明FBXO42可能导致HCC中复杂的免疫微环境。同时，我们的数据显示FBXO42水平与CAFs浸润和癌症干性呈正相关。此外，FBXO42促进了HCC的恶性行为。机制上，FBXO42与p57Kip2相互作用，依次促进p57Kip2的泛素化和降解，最终导致HCC进展。最后，已证明YY1通过转录调控上调FBXO42的表达。