Hepatitis B Virus X Protein Inhibits Tumor Suppressor miR-205 through Inducing Hypermethylation of miR-205 Promoter to Enhance Carcinogenesis

Zhang, Tao; Zhang, Junping; Cui, Ming; Liu, Fabao; You, Xiaona; Du, Yumei; Gao, Yuen; Zhang, Shuai; Lu, Zhenzhen; Ye, Lihong; Zhang, Xiaodong

doi:10.1593/neo.131362

Cited by 81 publications

(56 citation statements)

References 42 publications

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“…Many studies have emphasized the causal links between miRNA deregulation and cancer development. Our laboratory has reported that miR-520e (or miR-205) suppresses the growth of hepatoma cells through the targeting of NF-kB-inducing kinase (NIK) mRNA (or hepatitis B virus X protein mRNA) [8,9] . Recently, it has been reported that miR-506 inhibits epithelial mesenchymal transition (EMT) in ovarian cancer and breast cancer [10,11] .…”

Section: Introductionmentioning

confidence: 99%

MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR

et al. 2014

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Aim: MiR-506 is a miRNA involved in carcinogenesis of several kinds of cancer. In this study, we explored whether miR-506 played a critical role in hepatocellular carcinoma (HCC). Methods: Twenty HCC and adjacent normal liver tissue samples were collected. Human hepatoma cell lines HepG2 and H7402 were used for in vitro studies. The expression of miR-506 and transcriptional co-activator YAP was examined using qRT-PCR. Western blot analysis was used to measure the expression of YAP and its target genes. Luciferase reporter gene assay was used to identify YAP as a target gene of miR-506. MTT and EdU assays were carried out for functional analysis. Results: The expression of miR-506 was significantly lower in HCC than in adjacent normal liver tissues. Bioinformatics analysis revealed that YAP mRNA might be one of the targets of miR-506, and miR-506 in HCC tissues was found to be negatively correlated with YAP (r=-0.605). In both HepG2 and H7402 cells, miR-506 dose-dependently down-regulated YAP and its target genes c-Myc and the connective tissue growth factor (CTGF). Luciferase reporter gene assays demonstrated that miR-506 targeted the wild type 3′UTR of YAP mRNA, but not a 3′UTR with a mutant seed site. Furthermore, miR-506 significantly inhibited the proliferation of HepG2 and H7402 cells, while anti-miR-506 enhanced the cell proliferation, which was blocked by YAP siRNA. Conclusion: MiR-506 suppresses the proliferation of hepatoma cells by targeting YAP mRNA.

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Section: Introductionmentioning

confidence: 99%

MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR

et al. 2014

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“…A). We chose the promoter regions in our analysis as suggested by previous studies . As a result, the bisulfite sequencing revealed increased methylation level in promoter A at CpG sites 2, 4, 6–7 and in promoter B at CpG sites 3–6 in ErbB2‐overexpressing and RafCAAX‐overexpressing cells compared with vector control cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

ErbB2 signaling epigenetically suppresses microRNA‐205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer

et al. 2017

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We previously reported that micro RNA ‐205 (miR‐205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR‐205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR‐205 downregulation. In ErbB2‐overexpressing breast epithelial cells, miR‐205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD 98059, Raf‐1 inhibitor ZM ‐336372, and ERK inhibitor SCH 772984, but PI 3K inhibitor LY 294002 and p38 MAPK inhibitor SB 203580 had no effect. We established breast epithelial cells overexpressing Raf CAAX , a constitutively active form of Raf‐1, and showed that overexpression of Raf CAAX dramatically reduced miR‐205 expression. In Raf CAAX ‐overexpressing cells, miR‐205 expression was also significantly increased by SCH 772984. Moreover, miR‐205 expression was significantly increased by treatment with DNA methyltransferase ( DNMT ) inhibitor 5‐aza‐2′‐deoxycytidine and expression of several DNMT family members was increased in both ErbB2‐ and Raf CAAX ‐overexpressing cells. DNA methylation analysis by bisulfite sequencing revealed that the putative miR‐205 promoters were predominantly hypermethylated in both ErbB2‐ and Raf CAAX ‐overexpressing cells. Reporter activity of the putative miR‐205 promoters was reduced in both ErbB2‐overexpressing and Raf CAAX ‐overexpressing cells. Together, these findings indicate that ErbB2 signaling epigenetically suppresses miR‐205 transcription via the Ras/Raf/ MEK / ERK pathway.

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“…It is worth mentioning that HBx protein, as one of the most important oncogenic proteins for HBV X gene encoding, can regulate the expression of miRNAs at the transcriptional level, which has been suggested to regulate the HBV virus replication and proliferation to greatly affect the progression of HBV‐related HCC . For example, HBx has previously demonstrated to inhibit miR‐15b and miR‐205, or promote miR‐224, and thus regulating the growth of HBV‐mediated HCC cells . Therefore, we constructed liver cell line (Huh7‐X) and HCC cell line (HepG2‐X), both of which HBx was stably expressed, to further investigate the mechanism of miR‐520e in HCC.…”

Section: Discussionmentioning

confidence: 99%

Influence of miR‐520e‐mediated MAPK signalling pathway on HBV replication and regulation of hepatocellular carcinoma cells via targeting EphA2

Tian

Zhang

et al. 2019

Journal of Viral Hepatitis

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Summary We determined the role of miR‐520e in the replication of hepatitis B virus (HBV) and the growth of hepatocellular carcinoma (HCC) cells. MiR‐520e and EPH receptor A2 (EphA2) in HBV‐positive HCC tissues and cells were detected, and we studied the impact of miR‐520e and the EphA2 receptor in cellular and murine HBV replication models. We find that MiR‐520e was upregulated and EphA2 was downregulated in HBV‐positive HCC tissues and cells. MiR‐520e was decreased in Huh7‐X and HepG2‐X cells in which HBx was stably expressed, but was dose‐dependently elevated after interfering with HBx. Additionally, miR‐520e mimic and si‐EphA2 groups were reduced in association with increases in HBV DNA content, HBsAg and HBeAg levels, cell proliferation and were enhanced in the expressions of EphA2, p‐p38MAPK/p38MAPK, phosphorylated extracellular signal‐regulated kinase 1/2 (p‐ERK1/2)/ERK1/2 and cell apoptosis. Furthermore, si‐EphA2 reversed the promotion effect of miR‐520e inhibitor on HBV replication and tumour cell growth. Upregulating miR‐520e in rAAV8‐1.3HBV‐infected mouse resulted in reduced EphA2 in liver tissues and HBV DNA content in serum. We find that MiR‐520e was decreased in HBV‐positive HCC, while overexpression of miR‐520e blocked p38MAPK and ERK1/2 signalling pathways by an inhibitory effect on EphA2 and ultimately reduced HBV replication and inhibited tumour cell growth. These data indicate a role for miR‐520e in the regulation of HBV replication.

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Hepatitis B Virus X Protein Inhibits Tumor Suppressor miR-205 through Inducing Hypermethylation of miR-205 Promoter to Enhance Carcinogenesis

Cited by 81 publications

References 42 publications

MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR

MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR

ErbB2 signaling epigenetically suppresses microRNA‐205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer

Influence of miR‐520e‐mediated MAPK signalling pathway on HBV replication and regulation of hepatocellular carcinoma cells via targeting EphA2

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