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Hepatitis B virus X protein contributes to hepatocellular carcinoma via upregulation of KIAA1429 methyltransferase and mRNA m6A hypermethylation of HSPG2/Perlecan [RNA-Seq]

ABSTRACT: Chronic hepatitis B virus (HBV) remains to be the most common risk factor of hepatocellular carcinoma (HCC). While work has primarily focussed on understanding the direct and indirect mechanisms of Hepatitis B virus X protein (HBx) mediated hepatocarcinogenesis, from genetic and epigenetic perspectives, its influence on RNA modification mediated onset of liver malignancies is less well understood. This study explored the role of HBV-encoded HBx in altering the m6A methylome profile and its implications on the pathogenesis of HCC. We established HBx expressing stable HCC cell lines, Huh7-HBx and HepG2-HBx, and explored the transcriptomic and epitranscriptomic profiles by RNA-seq and MeRIP-seq, respectively. Preliminary results suggest that HBx promotes liver cell proliferation, migration, survival and overall m6A methylation in HCC cells and is involved in modulating the extracellular matrix. We show that HBx mediates liver cell transformation by upregulating KIAA1429 methyltransferase. HBx also drives the expression and hypermethylation of the extracellular matrix protein HSPG2/Perlecan and promotes tumourigenesis. Our findings indicate a potential interaction between KIAA1429 and HSPG2, thus could be novel targets in combating HBx-driven HCC and warrants further investigation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240394 | GEO | 2023/08/09

REPOSITORIES: GEO

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Hepatitis B virus X protein contributes to hepatocellular carcinoma via upregulation of KIAA1429 methyltransferase and mRNA m6A hypermethylation of HSPG2/Perlecan [MeRIP-Seq]

Project description:Chronic hepatitis B virus (HBV) remains to be the most common risk factor of hepatocellular carcinoma (HCC). While work has primarily focussed on understanding the direct and indirect mechanisms of Hepatitis B virus X protein (HBx) mediated hepatocarcinogenesis, from genetic and epigenetic perspectives, its influence on RNA modification mediated onset of liver malignancies is less well understood. This study explored the role of HBV-encoded HBx in altering the m6A methylome profile and its implications on the pathogenesis of HCC. We established HBx expressing stable HCC cell lines, Huh7-HBx and HepG2-HBx, and explored the transcriptomic and epitranscriptomic profiles by RNA-seq and MeRIP-seq, respectively. Preliminary results suggest that HBx promotes liver cell proliferation, migration, survival and overall m6A methylation in HCC cells and is involved in modulating the extracellular matrix. We show that HBx mediates liver cell transformation by upregulating KIAA1429 methyltransferase. HBx also drives the expression and hypermethylation of the extracellular matrix protein HSPG2/Perlecan and promotes tumourigenesis. Our findings indicate a potential interaction between KIAA1429 and HSPG2, thus could be novel targets in combating HBx-driven HCC and warrants further investigation.

2023-08-09 | GSE240450 | GEO

Genome-wide identification of transcripts associated with KIAA1429 by RIP-seq

Project description:N6-methyladenosine (m6A) modification, as the most abundant internal methylation of eukaryotic RNA transcripts, is critically implicated in RNA processing, decay, transport and translation. Here we showed that KIAA1429, the largest known component in the m6A methyltransferase complex, was considerably upregulated in hepatocellular carcinoma (HCC) tissues. High expression of KIAA1429 was significantly associated with the malignant clinical features and the poor prognosis of HCC patients. Silencing KIAA1429 suppressed the cell proliferation and metastasis in vitro and in vivo. Integrated MeRIP-seq, RIP-seq and RNA-seq data identified GATA3 as the direct downstream target of KIAA1429-mediated m6A modification. KIAA1429 knockdown markedly impaired the m6A levels of GATA3 mRNA and increased the expression of GATA3. Mechanistically, KIAA1429 induced the m6A methylation on 3’ UTR of GATA3 pre-mRNA, leading to the separation of RNA-binding protein HuR and the degradation of GATA3 pre-mRNA, which was followed by the downregulation of GATA3. Strikingly, a long noncoding RNA (lncRNA) GATA3-AS, transcribed from the antisense strand of GATA3 gene, functioned as a cis-acting element for the preferential interaction of KIAA1429 with GATA3 pre-mRNA. Accordingly, we found that the tumor growth and metastasis driven by KIAA1429 or GATA3-AS were mediated by GATA3. Patients with low KIAA1429 and high GATA3 expressions showed greatly better poor overall survival and disease-free survival. In conclusion, our study proposed a complex KIAA1429-GATA3 regulatory model based on m6A modification and provided insights into the epi-transcriptomic dysregulation in hepatocarcinogenesis and metastasis.

2019-07-27 | GSE134978 | GEO

Wild-type versus HBx-transfected mive

Project description:Hepatitis B virus (HBV) has been clearly recognized as an etiological factor for hepatocellular carcinoma (HCC). HBV encodes the potentially oncogenic HBx protein. We aimed to elucidate the molecular mechanism of HCC caused by HBx and to discover the biomarker related to HCC by HBx. Three experimental groups, 3, 9 and 13 month aged HBx Tg mice and age matched normal wild type B6 mouse which have same background of HBx Tg mice were used to find differentially expressed genes during HCC. Keywords: Genetic modification 3-month-old, 9-month-old, 13-month-old wild type B6 mice vs 3-month-old, 9-month-old, 13-month-old HBx transfected mice; Biological replicates at each timepoint; 9 controls vs 9 HBx-mice

2010-06-19 | E-GEOD-12723 | biostudies-arrayexpress

Huh-7 exosomes and HBV - Quantitative Proteomic Analysis of Exosome Protein Content Changes Induced by Hepatitis B Virus in Huh-7 Cells Using SILAC Labeling and LC-MS/MS

Project description:Hepatitis B virus (HBV) infection could cause hepatitis, liver cirrhosis and hepatocellular carcinoma. HBV-mediated pathogenesis is only partially understood, but X protein (HBx) reportedly possesses oncogenic potential. Exosomes are small membrane vesicles with diverse functions released by various cells including hepatocytes, and HBV harnesses cellular exosome biogenesis and export machineries for virion morphogenesis and secretion. Therefore, HBV infection might cause changes in exosome contents with functional implications for both virus and host. In this project, exosome protein content changes induced by HBV and HBx were quantitatively analyzed by SILAC/LC-MS/MS. Exosomes prepared from SILAC-labeled hepatoma cell line Huh-7 transfected with HBx, wildtype or HBx-null HBV replicon plasmids were analyzed by LC-MS/MS.

2014-10-09 | PXD001339 | Pride

Wild-type versus HBx-transfected mive

2008-09-11 | GSE12723 | GEO

Small RNA Solexa sequencing of human liver samples

Project description:We applied small RNA Solexa sequencing technology to identify microRNA expression in human liver samples from surgically removed liver tissues including three normal liver tissues (distal normal liver tissue of liver hemangioma), an hepatitis B virus (HBV)-infected liver, a severe chronic hepatitis B liver, two HBV-related hepatocellular carcinoma (HCC), an hepatitis C virus (HCV)-related HCC, and an HCC without HBV or HCV infection. All samples were collected with the informed consent of the patients and the experiments were approved by the ethics committee of Second Military Medical University, Shanghai, China. We investigated the miRNome in human normal liver and suggested some deregulated abundantly expressed microRNAs in HCC. center_name: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China. Examination of miRNome in human liver samples from surgically removed liver tissues including three normal liver tissues (distal normal liver tissue of liver hemangioma), an hepatitis B virus (HBV)-infected liver tissue, a severe chronic hepatitis B liver tissue, an HBV-related hepatocellular carcinoma (HCC) tissue and adjacent liver tissues of different regions,an HBV-related HCC tissue and adjacent liver tissue, an hepatitis C virus (HCV)-related HCC tissue and adjacent liver tissue, and an HCC without HBV or HCV infection and adjacent liver tissue. All 15 human liver tissue samples.

2010-04-10 | E-GEOD-21279 | biostudies-arrayexpress

Huh-7 exosomes and HBV

2017-03-29 | MSV000080794 | MassIVE

Identification of substrates of the CRL4-HBx E3 ubiquitin ligase

Project description:Hepatitis B Virus (HBV) remains a major public health problem, and is a major cause liver cancer worldwide. HBV infection in vivo requires the function of the HBx protein, which facilitates expression of viral genes from the episomal genome by an unknown mechanism. Evidence suggests that HBx functions as a targeting subunit for the CRL4 E3 ubiquitin ligase, redirecting the complex to target and degrade an unknown host restriction factor. We used substrate trapping proteomics to search for ubiquitylation substrates of HBx. We used MLN4924 to block CRL activity and stabilize interactions between HBx and its substrates. We then performed APMS to identify bound proteins and potential substrates.

2016-09-29 | PXD004762 | Pride

KIAA1429/VIRMA promotes breast cancer proliferation and migration by stabilizing m6A-modified HAS2 RNA expression in cytosol

Project description:N6-methyladenosine (m6A) is the most abundant internal RNA modification in mRNA molecules and plays important roles in multiple important biological processes including cancer development. KIAA1429/VIRMA is an important component of m6A methyltransferase complex to facilitate depositing m6A modification in RNA molecules. Here we found that KIAA1429/VIRMA was overexpressed in breast cancer patients among other m6A related enzymes. Breast cancer patients with higher KIAA1429 expression have worse survival compared with control group. In addition, KIAA1429/VIRMA protein mislocated in cytosol in breast cancer tissues and cell lines. KIAA1429/VIRMA depletion reduced breast cancer cell proliferation and migration. Mechanism studies showed that cytosolic expressed KIAA1429/VIRMA interacted with m6A reader protein IGF2BP3 and stabilized expression of m6A-modified HAS2 expression. HAS2 is downstream of KIAA1429/VIRMA to mediate breast cancer cell proliferation and migration and has positive correlation with KIAA1429/VIRMA expression in cancer patients.

2021-11-02 | GSE185494 | GEO

DNA methylome and transcriptome analysis of normal and HBx transgenic mouse liver

Project description:A genome-wide integrated methylome and transcriptome analysis of the early stage of hepatocellular carcinoma development that induced by HBx. The HBV x (HBx) protein, which plays a critical role in the development of HCC, was shown to interact with several epigenetic factors, such as DNMT3A and HDAC1. Most HBx transgenic (TG) mice spontaneously develop HCC at about 1 year of age, providing genetic validation of the oncogenic potential of HBx even in the absence of viral integration and chronic inflammation. Therefore, it would be intriguing to study the regulatory role of HBx in the epigenome and its impact on HCC development. We performed a genome-wide analysis to examine the differences in DNA methylation patterns and RNA transcriptions between cancer and normal liver cells. High-throughput sequencing analysis of MIRA (methylated CpG island recovery assay) and mRNA at 3 mouth old age mouse liver

2013-06-19 | E-GEOD-48052 | biostudies-arrayexpress

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