Dataset Information

USP40 promotes hepatocellular carcinoma cell proliferation, migration and stemness by deubiquitinating and stabilizing Claudin1.

ABSTRACT:

Background

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor that poses a major threat to people's lives and health. Previous studies have found that multiple deubiquitinating enzymes are involved in the pathogenesis of HCC. The purpose of this work was to elucidate the function and mechanism of the deubiquitinating enzyme USP40 in HCC progression.

Methods

The expression of USP40 in human HCC tissues and HCC cell lines was investigated using RT-qPCR, western blotting and immunohistochemistry (IHC). Both in vitro and in vivo experiments were conducted to determine the crucial role of USP40 in HCC progression. The interaction between USP40 and Claudin1 was identified by immunofluorescence, co-immunoprecipitation and ubiquitination assays.

Results

We discovered that USP40 is elevated in HCC tissues and predicts poor prognosis in HCC patients. USP40 knockdown inhibits HCC cell proliferation, migration and stemness, whereas USP40 overexpression shows the opposite impact. Furthermore, we confirmed that Claudin1 is a downstream gene of USP40. Mechanistically, USP40 interacts with Claudin1 and inhibits its polyubiquitination to stabilize Claudin1 protein.

Conclusions

Our study reveals that USP40 enhances HCC malignant development by deubiquitinating and stabilizing Claudin1, suggesting that targeting USP40 may be a novel approach for HCC therapy.

SUBMITTER: Wu Q

PROVIDER: S-EPMC10837946 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

USP40 promotes hepatocellular carcinoma cell proliferation, migration and stemness by deubiquitinating and stabilizing Claudin1.

Wu Qingsong Q Qiu Yuanyuan Y Guo Jinhui J Yuan Zibo Z Yang Yingnan Y Zhu Qingwei Q Zhang Zhe Z Guo Junwei J Wu Yanfang Y Zhang Junyu J Huang Dongsheng D Tu Kangsheng K Hu Xiaoge X

Biology direct 20240202 1

<h4>Background</h4>Hepatocellular carcinoma (HCC) is a prevalent malignant tumor that poses a major threat to people's lives and health. Previous studies have found that multiple deubiquitinating enzymes are involved in the pathogenesis of HCC. The purpose of this work was to elucidate the function and mechanism of the deubiquitinating enzyme USP40 in HCC progression.<h4>Methods</h4>The expression of USP40 in human HCC tissues and HCC cell lines was investigated using RT-qPCR, western blotting a ...[more]

PMID: 38308285

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Project description:BackgroundUSP51 is a deubiquitinase (DUB), that is involved in diverse cellular processes. Accumulating evidence has demonstrated that USP51 contributes to cancer development. However, its impact on non-small cell lung carcinoma (NSCLC) cell malignancy is largely unknown.MethodsIn this study, we performed bioinformatics analysis on a dataset from The Cancer Genome Atlas to determine the association between USP51 and cell stemness marker expression in NSCLC patients. RT‒qPCR, Western blotting, and flow cytometry were performed to examine the effects of USP51 depletion on stemness marker expression. Colony formation and tumor sphere formation assays were used to assess the stemness of NSCLC cells. A cycloheximide chase time-course assay and a polyubiquitination assay were carried out to analyze the effects of USP51 on the TWIST1 protein level. TWIST1 was overexpressed in USP51 knockdown NSCLC cells to determine whether TWIST1 is required. The effect of USP51 on the in vivo growth of NSCLC cells was tested through subcutaneous injections in mice.ResultsWe found that USP51 deubiquitinates TWIST1, which is significantly upregulated in the tissues of patients with NSCLC and is closely associated with poor prognosis. USP51 expression was positively correlated with the expression of stemness marker CD44, SOX2, NANOG, and OCT4 in NSCLC patients. USP51 depletion attenuated mRNA, protein, and cell surface expression of stemness markers and the stemness of NSCLC cells. Ectopic USP51 expression potentiated the stability of the TWIST1 protein by attenuating its polyubiquitination. In addition, TWIST1 re-expression in NSCLC cells reversed the inhibitory effect of USP51 knockdown on cell stemness. Furthermore, the in vivo results confirmed the suppressive effect of USP51 depletion on NSCLC cell growth.ConclusionsOur results show that USP51 maintains the stemness of NSCLC cells by deubiquitinating TWIST1. Knocking it down reduces both cell stemness and growth of NSCLC cells.

Project description:ObjectivesRecent evidence suggests that Sort1 promotes carcinogenesis and tumor progression in multiple types of cancers. This study investigates the role of Sort1 in hepatocellular carcinoma (HCC).MethodsThe differentially expressed gene was screened through GEO and TCGA databases. The Sort1 gene was identified and its expression was then verified by TCGA and HCCDB (a database of hepatocellular carcinoma expression atlas) databases. The Human Protein Atlas database was used to assess the gene expression in tissues. The TCGA and KM-plotter databases were used to study the relationship between Sort1 and HCC. The correlation between Sort1 and immune cells was evaluated through the TIMER database. GO and KEGG enrichment analysis was used to investigate the possible mechanism. The role of Sort1 in cell proliferation and invasion of HCC was further explored through in vitro experiments.ResultThe differentially expressed molecule obtained from database screening was Sort1. Its expression was higher in cancer tissues than in paracancerous ones, and it was mainly located in the cytoplasm. The TCGA, KM-plotter databases, and our study data showed that low expression of Sort1 in HCC patients had better overall survival (OS), progression-free survival (PFI), and disease-specific survival (DSS). Further analysis indicated a significant correlation between Sort1 expression and immune cell infiltration. The gene set enrichment analysis (GSEA) analysis showed that Sort1 affected the biological events of HCC by participating in the WNT, TGF-BETA, JAK, STAT, and CALCIUM signaling pathways. In vitro, cytological experiments demonstrated reduced expression of PCNA, Ki-67, Vimentin, N-cadherin, and MMP-9 mRNA after knocking down Sort1, although E-cadherin expression was promoted. Overall, these processes reduced the ability of proliferation and invasion of HCC cells.ConclusionDownregulation of Sort1 can prolong the OS, PFI, and DSS of HCC patients. Furthermore, due to its link with immune cell infiltration, the Sort1 gene represents a potentially novel predictive biomarker of HCC. The growth of HCC can be significantly inhibited by interfering with Sort1; therefore, these results provide a potential target for developing anticancer strategies for HCC.

Dataset Information

USP40 promotes hepatocellular carcinoma cell proliferation, migration and stemness by deubiquitinating and stabilizing Claudin1.

Background

Methods

Results

Conclusions

Publications

USP40 promotes hepatocellular carcinoma cell proliferation, migration and stemness by deubiquitinating and stabilizing Claudin1.

Similar Datasets

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