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Hepatitis B virus X protein inhibits tumor suppressor miR-205 through inducing hypermethylation of miR-205 promoter to enhance carcinogenesis.

ABSTRACT: The infection of hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC), in which HBV X protein (HBx) plays crucial roles. MicroRNAs are involved in diverse biologic functions and in carcinogenesis by regulating gene expression. In the present study, we aim to investigate the underlying mechanism by which HBx enhances hepatocarcinogenesis. We found that miR-205 was downregulated in 33 clinical HCC tissues in comparison with adjacent noncancerous hepatic tissues. The expression levels of miR-205 were inversely correlated with those of HBx in abovementioned tissues. Then, we demonstrated that HBx was able to suppress miR-205 expression in hepatoma and liver cells. We validated that miR-205 directly targeted HBx mRNA. Ectopic expression of miR-205 downregulated HBx, whereas depletion of endogenous miR-205 upregulated HBx in hepatoma cells. Notably, our data revealed that HBx downregulated miR-205 through inducing hypermethylation of miR-205 promoter in the cells. In terms of function, the forced miR-205 expression remarkably inhibited the HBx-enhanced proliferation of hepatoma cells in vitro and in vivo, suggesting that miR-205 is a potential tumor-suppressive gene in HCC. HBx-transgenic mice showed that miR-205 was downregulated in the liver. Importantly, HBx was able to abrogate the effect of miR-205 on tumor suppression in carcinogenesis. Therefore, we conclude that HBx is able to inhibit tumor suppressor miR-205 to enhance hepatocarcinogenesis through inducing hypermethylation of miR-205 promoter during their interaction. Therapeutically, miR-205 may be useful in the treatment of HCC.

SUBMITTER: Zhang T

PROVIDER: S-EPMC3858896 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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Hepatitis B virus X protein inhibits tumor suppressor miR-205 through inducing hypermethylation of miR-205 promoter to enhance carcinogenesis.

Zhang Tao T Zhang Junping J Cui Ming M Liu Fabao F You Xiaona X Du Yumei Y Gao Yuen Y Zhang Shuai S Lu Zhanping Z Ye Lihong L Zhang Xiaodong X

Neoplasia (New York, N.Y.) 20131101 11

The infection of hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC), in which HBV X protein (HBx) plays crucial roles. MicroRNAs are involved in diverse biologic functions and in carcinogenesis by regulating gene expression. In the present study, we aim to investigate the underlying mechanism by which HBx enhances hepatocarcinogenesis. We found that miR-205 was downregulated in 33 clinical HCC tissues in comparison with adjacent noncancerous hepa ...[more]

PMID: 24339740

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Project description:Background: By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into exosomes and are implicated in different aspects of tumour angiogenesis. However, the underlying mechanisms are incompletely understood. Methods: The GEPIA database and in situ hybridization assay were used to analyse expression of miR-205 in ovarian tissues. Immunohistochemistry was performed to examine the relationship between miR-205 and microvessel density. Expression of circulating miR-205 was evaluated by RT-PCR and GEO database analysis. Co-culture and exosome labelling experiments were performed to assess exosomal miR-205 transfer from ovarian cancer (OC) cells to endothelial cells ECs. Exosome uptake assays were employed to define the cellular pathways associated with the endocytic uptake of exosomal miR-205. The role of exosomal miR-205 in angiogenesis was further investigated in vivo and in vitro. Western blotting and rescue experiments were applied to detect regulation of the PTEN-AKT pathway by exosomal miR-205 in ECs. Results: miR-205 was up-regulated in OC tissues, and high expression of miR-205 was associated with metastatic progression in OC patients. Moreover, miR-205 was highly enriched in cancer-adjacent ECs, and up-regulation of miR-205 correlated positively with high microvessel density in OC patients. Importantly, miR-205 was markedly enriched in the serum of OC patients, and a high level of miR-205 in circulating exosomes was associated with OC metastasis. In addition, OC-derived miR-205 was secreted into the extracellular space and efficiently transferred to adjacent ECs in an exosome-dependent manner, and the lipid raft-associated pathway plays an important role in regulating uptake of exosomal miR-205. Exosomal miR-205 from OC cells significantly promoted in vitro angiogenesis and accelerated angiogenesis and tumour growth in a mouse model. Furthermore, we found that exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway. Conclusion: These findings demonstrate an exosome-dependent mechanism by which miR-205 derived from cancer cells regulates tumour angiogenesis and implicate exosomal miR-205 as a potential therapeutic target for OC.

Project description:BackgroundThe novel long noncoding RNA MEF2C-AS1 has been identified to play suppressor roles during tumorigenesis. DNA methylation has a regulatory effect on gene expression in cancer initiation and progression. However, the methylation status of MEF2C-AS1 and its role in colorectal cancer (CRC) development remain unclear.MethodsThe expression and methylation levels of MEF2C-AS1 were systematically analyzed among 31 cancers with available qualified data in GEPIA and UCSC Xena databases. Then, the MEF2C-AS1 methylation status was firstly examined among 12 CRCs by Illumina Infinium MethylationEPIC BeadChip in in-house step 1 and further quantified among 48 CRCs by the MassARRAY method in in-house step 2. Subsequently, its methylation and expression levels were quantified among 81 non-advanced adenomas (NAAs), 81 advanced adenomas (AAs), and 286 CRCs using the MassARRAY method, and among 34 NAAs, 45 AAs, and 75 CRCs by qRT-PCR, in in-house step 3, respectively. The effect of MEF2C-AS1 methylation on CRC survival was analyzed by the Kaplan-Meier method. Additionally, in vitro cell proliferation, migration and invasion assays, and bioinformatics analysis were performed to explore the role of MEF2C-AS1 in colorectal carcinogenesis.ResultsLower expression and higher methylation of MEF2C-AS1 were found in CRC by online databases. In the comparisons of lesion tissues with adjacent normal tissues, MEF2C-AS1 hypermethylation of each individual site and mean level was found among CRC patients in in-house step 1 and step 2, more meaningfully, among NAA patients, AA patients, and CRC patients at all stages during colorectal carcinogenesis in in-house step 3 (all p < 0.05). Further comparisons demonstrated significant differences between CRC and NAA (p = 0.025), AA and NAA (p = 0.020). Moreover, MEF2C-AS1 hypermethylation was associated with poorer disease-specific survival of CRC patients (p = 0.044). In addition, hypermethylation and lower expression of MEF2C-AS1 were verified in RKO cells, and the MEF2C-AS1 overexpression significantly suppressed RKO cell proliferation, migration, and invasion.ConclusionsThe findings reveal that MEF2C-AS1 hypermethylation might be an early driven event during colorectal carcinogenesis. It might serve as a promising prognostic biomarker for CRC survival. Our study also indicates the potential tumor-suppressing role of MEF2C-AS1 in CRC.

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Hepatitis B virus X protein inhibits tumor suppressor miR-205 through inducing hypermethylation of miR-205 promoter to enhance carcinogenesis.

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Hepatitis B virus X protein inhibits tumor suppressor miR-205 through inducing hypermethylation of miR-205 promoter to enhance carcinogenesis.

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