Dataset Information

Long non?coding RNA HOXA11?AS accelerates cell proliferation and epithelial?mesenchymal transition in hepatocellular carcinoma by modulating the miR?506?3p/Slug axis.

ABSTRACT: Hepatocellular carcinoma (HCC) is an aggressively malignant type of cancer with a complex pathogenesis. Multiple studies have identified that lncRNA HOXA11?AS is involved in the development of HCC. Nevertheless, the pathological mechanisms of HOXA11?AS in the development of HCC require further investigation. In the present study, the role and underlying mechanisms of HOXA11?AS in HCC were examined. RT?qPCR revealed that HOXA11?AS expression was increased, while that of miR?506?3p was decreased in HCC tissues and cells compared with that in adjacent non?tumor tissues and normal hepatic cells. Dual?luciferase reporter assay and RNA pull?down assay indicated that HOXA11?AS directly interacted with miR?506?3p. miR?506?3p downregulation reversed the inhibitory effects of HOXA11?AS deletion on cell proliferation, invasion and epithelial?mesenchymal transition (EMT), as shown by CCK?8 and Transwell assays, as well as western blot analysis. Bioinformatics analysis and dual?luciferase reporter assay indicated that Slug was a target gene of miR?506?3p. The overexpression of Slug reversed the effects of HOXA11?AS deletion on the viability, invasion and the EMT of HCC cells. Taken together, the present study demonstrates that HOXA11?AS functions as an oncogene to promote the progression of HCC via the miR?506?3p/Slug axis, providing a therapeutic target for patients with HCC.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7521580 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Long non‑coding RNA HOXA11‑AS accelerates cell proliferation and epithelial‑mesenchymal transition in hepatocellular carcinoma by modulating the miR‑506‑3p/Slug axis.

Liu Yinghui Y Yan Wenzhao W Zhou Dongfang D Jin Guohua G Cheng Xin X

International journal of molecular medicine 20200828 5

Hepatocellular carcinoma (HCC) is an aggressively malignant type of cancer with a complex pathogenesis. Multiple studies have identified that lncRNA HOXA11‑AS is involved in the development of HCC. Nevertheless, the pathological mechanisms of HOXA11‑AS in the development of HCC require further investigation. In the present study, the role and underlying mechanisms of HOXA11‑AS in HCC were examined. RT‑qPCR revealed that HOXA11‑AS expression was increased, while that of miR‑506‑3p was decreased i ...[more]

PMID: 32901858

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Project description:BackgroundColorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Exosome shave emerged as crucial regulators of intercellular communication and that abundant Circular RNAs (circRNAs) are enriched within exosomes. CircRNAs are novel members of noncoding RNAs regulating cancer proliferation and progression. However, the function and regulatory mechanism of cancer-derived exosomal circRNAs in CRC remains unclear.MethodsCRC cells-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blot. CCK-8, wound healing and transwell assays, and flow cytometry assays were conducted to assess whether exosomes would affect the proliferation, metastasis, and apoptosis of CRC cells, respectively. Moreover, we performed the RNA sequencing and RT-qPCR to identify circRNAs in exosome-stimulated CRC cells. Fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circPACRGL. Bioinformatic analyses (StarBase 2.0) were used to pool the miRNA targets of circPACRGL. Luciferase assays were performed to verify the direct interaction. Finally, flow cytometry was used to detect the differentiation of N1-N2 neutrophils.ResultsOur study identified a novel CRC-derived exosomal circRNA, circPACRGL. We found circPACRGL was significantly upregulated in CRC cells after tumor-derived exosomes addition. Moreover, circPACRGL serves as a sponge for miR-142-3p/miR-506-3p to facilitate the transforming growth factor-β1 (TGF-β1) expression. As a result, circPACRGL promoted CRC cell proliferation, migration and invasion, as well as differentiation of N1 to N2 neutrophils via miR-142-3p/miR-506-3p-TGF-β1 axis.ConclusionOur study, the first to reveal that cancer-derived exosomal circPACRGL plays an oncogenic role in CRC proliferation and metastasis, providing mechanistic insights into the roles of circRNAs in CRC progression and a valuable marker for CRC treatment.

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.

Dataset Information

Long non?coding RNA HOXA11?AS accelerates cell proliferation and epithelial?mesenchymal transition in hepatocellular carcinoma by modulating the miR?506?3p/Slug axis.

Publications

Long non‑coding RNA HOXA11‑AS accelerates cell proliferation and epithelial‑mesenchymal transition in hepatocellular carcinoma by modulating the miR‑506‑3p/Slug axis.

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