Hepatitis B virus X protein promotes epithelial‑mesenchymal transition and metastasis in hepatocellular carcinoma cell line HCCLM3 by targeting HMGA2

Zha, Yong; Yao, Qian; Liu, Jin‐Sheng; Wang, Yuan‐Yuan; Sun, Weiming

doi:10.3892/ol.2018.9359

Cited by 12 publications

(10 citation statements)

References 25 publications

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“…23 The role of HMGA2 in HCC has also been addressed in previous studies. It is reported that hepatitis B virus X protein promotes EMT of HCC cells by targeting HMGA2; 37 Meanwhile, a recent study have shown that the HMGA2-sh-3p20 fragment in the 3ʹUTR of HMGA2 mRNA promotes the growth of HCC cells by up-regulating HMGA2. 38 However, whether EGOT affects the expression of HMGA2 has not been addressed.…”

Section: Discussionmentioning

confidence: 99%

Long Non-Coding RNA EGOT Promotes the Malignant Phenotypes of Hepatocellular Carcinoma Cells and Increases the Expression of HMGA2 via Down-Regulating miR-33a-5p

Wu¹,

Ai²,

Zhang³

et al. 2019

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Background: Chronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). EGOT is a long non-coding RNA (lncRNA) induced after HCV infection that increases viral replication by antagonizing the antiviral response. Interestingly, EGOTalso acts as a crucial regulator in multiple cancers. However, its role in HCC remains unclear. Methods: Real-time PCR (RT-PCR) was used to detect the expression of EGOT in HCC samples and cell lines. CCK-8 assay and colony formation assay were performed to evaluate the effect of EGOT on proliferation. Scratch healing assay and transwell assay were used to detect the changes of migration and invasion. Flow cytometry was used to detect the effect of EGOT on apoptosis. Interaction between EGOT and miR-33a-5p was determined by bioinformatics analysis, RT-PCR, and dual-luciferase reporter assay. Western blot was used to confirm that high mobility group protein A2 (HMGA2) could be modulated by EGOT. Results: Compared with normal liver tissues, the expression level of EGOT in HCC tissues was significantly up-regulated. EGOT markedly regulated viability, migration and invasion of HCC cells. The expression level of EGOT was negatively correlated the expression level of miR-33a-5p. It is also confirmed that EGOT could specifically bind to miR-33a-5p and could reduce its expression, in turn, up-regulate the expression of HMGA2. Conclusion: Our data imply that EGOT may be a novel therapeutic target for HCC, and highlights the key role of EGOT/miR-33a-5p/HMGA2 in the progression of this deadly disease.

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Section: Discussionmentioning

confidence: 99%

Long Non-Coding RNA EGOT Promotes the Malignant Phenotypes of Hepatocellular Carcinoma Cells and Increases the Expression of HMGA2 via Down-Regulating miR-33a-5p

Wu¹,

Ai²,

Zhang³

et al. 2019

OTT

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“…Ã P < 0.05; ÃÃÃ P < 0.001; ÃÃÃÃ P < 0.0001. highest and lowest in HCC-LM3 compared to the other two HCC cell lines, respectively. Due to the high invasion capacity of HCC-LM3 cells (Zha et al, 2018), this suggested that miR-221-3p and miR-375 could be critical regulators of HCC cell invasion. HepG2.2.15 is an HCC cell line that carries and secretes HBV particles.…”

Section: The Expression Level Of Mir-221-3p and Mir-375 In Hcc Cells mentioning

confidence: 99%

Aberrant expression of two miRNAs promotes proliferation, hepatitis B virus amplification, migration and invasion of hepatocellular carcinoma cells: evidence from bioinformatic analysis and experimental validation

Liu

Cao

Cai

et al. 2020

PeerJ

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Background As key negative regulators of gene expression, microRNAs (miRNAs) play an important role in the onset and progression of hepatocellular carcinoma (HCC). This study aimed to identify the miRNAs involved in HCC carcinogenesis and their regulated genes. Methods The Gene Expression Omnibus (GEO) dataset (GSE108724) was chosen and explored to identify differentially expressed miRNAs using GEO2R. For the prediction of potential miRNA target genes, the miRTarBase was explored. Enrichment analysis of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed by the DAVID online tool. The hub genes were screened out using the CytoHubba plug-in ranked by degrees. The networks between miRNAs and hub genes were constructed by Cytoscape software. MiRNA mimics and negative control were transfected into HCC cell lines and their effects on proliferation, hepatitis B virus DNA (HBV-DNA) replication, TP53 expression, migration, and invasion were investigated. The following methods were employed: MTT assay, quantitative PCR (qPCR) assay, western blotting, wound healing assay, and transwell assay. Results A total of 50 differentially expressed miRNAs were identified, including 20 upregulated and 30 downregulated miRNAs, in HCC tumor tissues compared to matched adjacent tumor-free tissues. The top three upregulated (miR-221-3p, miR-222-3p, and miR-18-5p) and downregulated (miR-375, miR-214-3p and miR-378d) miRNAs, ranked by |log2 fold change (log2FC)|, were chosen and their potential target genes were predicted. Two gene sets, targeted by the upregulated and the downregulated miRNAs, were identified respectively. GO and KEGG pathway analysis showed that the predicted target genes of upregulated and downregulated miRNAs were mainly enriched in the cell cycle and cancer-related pathways. The top ten hub nodes of gene sets ranked by degrees were identified as hub genes. Analysis of miRNA-hub gene network showed that miR-221-3p and miR-375 modulated most of the hub genes, especially involving regulation of TP53. The q-PCR results showed that miR-221-3p and miR-375 were markedly upregulated and downregulated, respectively, in HCC cells and HCC clinical tissue samples compared to non-tumoral tissues. Furthermore, miR-221-3p overexpression significantly enhanced proliferation, HBV-DNA replication, as well as the migration and invasion of HCC cells, whereas miR-375 overexpression resulted in opposite effects. Western blotting analysis showed that the overexpression of miR-221-3p and miR-375 reduced and increased TP53 expression, respectively. Conclusion The present study revealed that miR-211-3p and miR-375 may exert vital effects on cell proliferation, HBV-DNA replication, cell migration, and invasion through the regulation of TP53 expression in HCC.

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“…Research showed that HBx could induce HMGA2 by regulating EMT, subsequently leading to HCC cell invasion. 37 These evidence suggest that HBx might regulate YAP1 in the EMT process. Indeed, we proved that HBx regulated promoter region of YAP was located at nt −348 through luciferase reporter gene assays.…”

Section: Dovepressmentioning

confidence: 92%

YAP1 Promotes Tumor Invasion and Metastasis in Nasopharyngeal Carcinoma with Hepatitis B Virus Infection

Huang¹,

Su²,

Liu³

et al. 2020

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Introduction: Nasopharyngeal carcinoma (NPC) patients with HBsAg (+) commonly present with high frequencies of distant metastasis and poor survival rate; however, the mechanism has not been elucidated. Materials and Methods: We analyzed the yes-associated protein 1 (YAP1) expression between HBsAg (+) and HBsAg (-) of NPC patients, then analyzed the relationship of YAP1 with survival. We further explored the anti-tumor role in NPC cell lines using YAP1 siRNA technique, and checked whether YAP1 regulatesepithelial-mesenchymal transition (EMT). The relationship between HBV X protein (HBx) and YAP1 was also tested using Dual-Luciferase reporter assay. Finally, we explored anti-YAP1 to inhibit tumor metastasis using the xenograft mice model. Results: In the current study, we found that YAP1 expression was higher in HBsAg (+) samples than in the HBsAg (-) samples, as a clinical signature, suggesting that YAP1 could be used as a prognostic factor for NPC. Our results showed that the HBx could regulate YAP1, further promoting cellular invasiveness through EMT. Anti-YAP1 can also decrease metastasis in vivo. Conclusion: Our findings suggest that YAP1 is a promising prognostic factor in NPC and could be used as a potential treatment target for NPC with HBV infection.

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Hepatitis B virus X protein promotes epithelial‑mesenchymal transition and metastasis in hepatocellular carcinoma cell line HCCLM3 by targeting HMGA2

Cited by 12 publications

References 25 publications

<p>Long Non-Coding RNA EGOT Promotes the Malignant Phenotypes of Hepatocellular Carcinoma Cells and Increases the Expression of HMGA2 via Down-Regulating miR-33a-5p</p>

<p>Long Non-Coding RNA EGOT Promotes the Malignant Phenotypes of Hepatocellular Carcinoma Cells and Increases the Expression of HMGA2 via Down-Regulating miR-33a-5p</p>

Aberrant expression of two miRNAs promotes proliferation, hepatitis B virus amplification, migration and invasion of hepatocellular carcinoma cells: evidence from bioinformatic analysis and experimental validation

<p>YAP1 Promotes Tumor Invasion and Metastasis in Nasopharyngeal Carcinoma with Hepatitis B Virus Infection</p>

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