Dataset Information

Pseudogene AKR1B10P1 enhances tumorigenicity and regulates epithelial-mesenchymal transition in hepatocellular carcinoma via stabilizing SOX4.

ABSTRACT: Pseudogenes exert potential functions in tumorigenicity and tumour process in human beings. In our previous research on oncogene AKR1B10 in hepatocellular carcinoma (HCC), its pseudogene, AKR1B10P1, was preliminarily noticed being anomalistic transcribed, whereas whether AKR1B10P1 plays any specific function in HCC is poorly understood. By using shRNA transfection and lentiviral infection, we regulated the expression of ARK1B10P1 transcript and the relative targets in two ways. As we discovered, pathological transcription of AKR1B10P1 in HCC cells significantly promotes cell growth and motility either in vitro or in vivo. AKR1B10P1 was correlated with relatively dismal features of HCC. The epithelial-mesenchymal transition (EMT) was enhanced by up-regulating AKR1B10P1. And, a potential sequence of AKR1B10P1 transcript was discovered directly interacting with miR-138. SOX4, a pivotal promotor of EMT, was validated as the down-streaming target of miR-138. Mechanistically, degradation of SOX4 mRNA induced by miR-138 was effectively abrogated by AKR1B10P1. In conclusion, pseudogene AKR1B10P1 exerts stabilizing effect on SOX4 in HCC, associated EMT process, by directly sponging miR-138, which post-transcriptionally modulates SOX4's regulating gene.

SUBMITTER: Hao F

PROVIDER: S-EPMC7579691 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Pseudogene AKR1B10P1 enhances tumorigenicity and regulates epithelial-mesenchymal transition in hepatocellular carcinoma via stabilizing SOX4.

Hao Fengjie F Fei Xiaochun X Ren Xinping X Xi Xiao Joanna J Chen Yongjun Y Wang Junqing J Wang Junqing J

Journal of cellular and molecular medicine 20200913 20

Pseudogenes exert potential functions in tumorigenicity and tumour process in human beings. In our previous research on oncogene AKR1B10 in hepatocellular carcinoma (HCC), its pseudogene, AKR1B10P1, was preliminarily noticed being anomalistic transcribed, whereas whether AKR1B10P1 plays any specific function in HCC is poorly understood. By using shRNA transfection and lentiviral infection, we regulated the expression of ARK1B10P1 transcript and the relative targets in two ways. As we discovered, ...[more]

PMID: 32924268

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Project description:Rationale: The role of SLUG in epithelial-mesenchymal transition during tumor progression has been thoroughly studied, but its precise regulation remains poorly explored. Methods: The affinity purification, mass spectrometry and CO-IP were performed to identify the interaction between SLUG and ubiquitin-specific protease 5 (USP5). Cycloheximide chase assays and deubiquitination assays confirmed that the effect of USP5 on the deubiquitin of SLUG. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional regulation of E-cadherin by SLUG effected by USP5. EMT related markers was detected by western blotting and immunofluorescence. Molecular docking, SPR sensor (biacore) and co-location were detected to prove Formononetin targets USP5. Bioinformatics analysis was used to study the relation of USP5 and SLUG to malignancy degree of HCC. Cell migration, invasion in HCC cells and xenografts model in nude mouse were conducted to detect the promotion of USP5 and the inhibition of Formononetin on EMT. Results: USP5 interacts with and stabilizes SLUG to regulate its abundance through USP5 deubiquitination activities in epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC). USP5 is highly expressed and positively correlated with SLUG expression in HCC with high malignancy. Knockdown of USP5 inhibits SLUG deubiquitination and inhibits HCC cells proliferation, metastasis, and invasion, while overexpression of USP5 promotes SLUG stability and EMT in vitro and in vivo. Through virtual screening, we found that Formononetin exhibits excellent binding to USP5. Moreover, Formononetin inhibits deubiquitinating activities of USP5 to SLUG and consequently impedes the EMT and malignant progression of HCC. Conclusion: Our findings reveal that USP5 serve as a potential target for tumor intervention and provide a preliminary antitumor therapy for inhibit EMT by targeting USP5 or its interaction with SLUG in HCC.

Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer?related deaths globally. Epithelial?to?mesenchymal transition (EMT) is a cellular process that confers HCC tumor cells with the ability to evade the immune system. Immune escape in most tumors, including HCC, is controlled by immune checkpoint molecules. The aim of the present study was to investigate the association between EMT and immune checkpoint in HCC, and identify novel therapeutic targets for HCC. An in vitro model of reversible EMT was utilized based on cytokine tumor necrosis factor (TNF)?? treatment of HCC cell lines Hep3B and PLC/PRF/5. Hep3B and PLC/PRF/5 cells were treated with TNF??, and the EMT status and the expression of immune checkpoint molecules was assessed by reverse transcription?quantitative PCR, western blotting and immunofluorescence. To confirm an association between EMT and immune modulators, cells were exposed to culture medium with TNF?? for 3 days to induce EMT, following which a reversal assay was performed. The expression of immune modulators and mesenchymal?to?epithelial transition (MET) status was investigated upon reversal of EMT. Furthermore, SurvExpress, a web?based platform was utilized to analyze survival and recurrence in a dataset of patients with HCC. TNF?? treatment for 3 days induced EMT in Hep3B and PLC/PRF/5 cells, as demonstrated by the downregulation of epithelial markers along with upregulation in mesenchymal markers. An EMT reversal assay was able to induce MET by increasing epithelial markers and decreasing mesenchymal markers. TNF???induced EMT led to the upregulation of immune modulators, including programmed death receptor ligand (PD?L)1, PD?L2, CD73 and B7?H3. In contrast, reversal of EMT suppressed the expression of PD?L1, PD?L2, CD73 and B7?H3. In addition, high expression of TNF?? and PD?L1 in 422 patients with HCC was associated with poor overall survival. The coordinate expression of TNF?? with PD?L2 in this patient cohort was associated with increased HCC recurrence. In conclusion, the present study demonstrated a close association between immune modulator expression and EMT induction/reversal driven by TNF??.

Dataset Information

Pseudogene AKR1B10P1 enhances tumorigenicity and regulates epithelial-mesenchymal transition in hepatocellular carcinoma via stabilizing SOX4.

Publications

Pseudogene AKR1B10P1 enhances tumorigenicity and regulates epithelial-mesenchymal transition in hepatocellular carcinoma via stabilizing SOX4.

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