Hepatitis B Virus Regulates Apoptosis and Tumorigenesis through the MicroRNA-15a-Smad7-Transforming Growth Factor Beta Pathway

Liu, Ningning; Jiao, Tong; Huang, Yan; Liu, Wenjun; Li, Zhiwei; Ye, Xin

doi:10.1128/jvi.02784-14

Cited by 47 publications

(38 citation statements)

References 39 publications

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“…The human hepatoma cell line HepG2, human embryonic kidney cell line 293T, human normal liver cell line L02, and Mus musculus neuronal and amoeboid stem cell line Neuro‐2a used in this study were purchased from ATCC (USA). The HepG2‐4D14 cell lines, in which the HBV genome was stably integrated, were kindly provided by Dongping Xu (302 Hospital of PLA, China) …”

Section: Methodsmentioning

confidence: 99%

Hepatitis B Virus–Upregulated LNC‐HUR1 Promotes Cell Proliferation and Tumorigenesis by Blocking p53 Activity

Liu

Yang

et al. 2018

Hepatology

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Recent studies have indicated that a number of long noncoding RNAs (lncRNAs) are dysregulated in hepatocellular carcinoma, while their aberrant expressions are associated with tumorigenesis and poor prognosis. To identify hepatitis B virus (HBV)-related lncRNAs, we used RNA deep sequencing to quantify the abundances of lncRNAs in HepG2 cells and HBV transgenic HepG2-4D14 cells. Here, we demonstrate that lnc-HUR1 is significantly upregulated in HepG2-4D14 cells. We found that HBV-encoded hepatitis B x protein can enhance the transcription of lnc-HUR1. Overexpression of lnc-HUR1 promotes cell proliferation, whereas knockdown of lnc-HUR1 inhibits cell growth. We identified that lnc-HUR1 can interact with p53 and inhibit its transcriptional regulation on downstream genes, such as p21 and B cell lymphoma 2-associated X protein. We generated lnc-HUR1 transgenic mice and performed the partial hepatectomy (PHx) to examine liver regeneration. The data showed that the ratio of liver weight to body weight in lnc-HUR1 transgenic mice is higher than that in wild-type (WT) littermates at day 2 and day 3 following hepatectomy. Consistently, the results of bromodeoxyuridine staining on liver sections following hepatectomy indicate that the ratio of bromodeoxyuridine-positive cells in lnc-HUR1 transgenic mice is significantly higher than that in WT mice, suggesting that lnc-HUR1 promotes cell proliferation during liver regeneration. Next, we performed the experiment of diethylnitrosamine-induced tumorigenesis. The data demonstrate that tumor number in lnc-HUR1 transgenic mice is higher compared with control mice, indicating that lnc-HUR1 enhances diethylnitrosamine-induced tumorigenesis. Conclusion: We reveal that HBV-upregulated lnc-HUR1 promotes cell proliferation and tumorigenesis by interacting with p53 to block downstream gene transcription. Our findings suggest that lnc-HUR1 plays an important role in HBV-related hepatocellular carcinoma development and may serve as a therapeutic marker for hepatocellular carcinoma. (Hepatology 2018; 00:000-000).

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Section: Methodsmentioning

confidence: 99%

Hepatitis B Virus–Upregulated LNC‐HUR1 Promotes Cell Proliferation and Tumorigenesis by Blocking p53 Activity

Liu

Yang

et al. 2018

Hepatology

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“…It has proved that miR-15a has a positive effect on TGF-β/Smad pathway in HBV-infected patients [34]. Hepatitis C virus (HCV) infection causes chronic hepatitis, which may progress to hepatic fibrosis, even HCC.…”

Section: The Mir-15 Family Members Have a Positive Impact On Tgf-β Simentioning

confidence: 99%

The roles of microRNA families in hepatic fibrosis

Jiang

Wan

et al. 2017

Cell Biosci

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When hepatocytes are damaged severely, a variety of signaling pathways will be triggered by inflammatory factors and cytokines involving in the process of hepatic fibrosis. The microRNA (miRNA) family consists of several miRNAs which have the potential for synergistic regulation of these signaling pathways. However, it is poor to understand the roles of miRNA family as a whole in hepatic fibrosis. Increasing studies have suggested several miRNA families are related with activation of hepatic stellate cells and hepatic fibrosis through cooperatively regulating certain signaling pathways. During the process of hepatic fibrosis, miR-29 family primarily induces cell apoptosis by modulating phosphatidylinositol 3-kinase/AKT signaling pathway and regulates extracellular matrix accumulation. miR-34 family promotes the progression of hepatic fibrosis by inducing activation of hepatic stellate cells, while miR-378 family suppresses the process in Glis dependent manner. miR-15 family mainly promotes cell proliferation and induces apoptosis. The miR-199 family and miR-200 family are responsible for extracellular matrix deposition and the release of pro-fibrotic cytokines. These miRNA family members play pro-fibrotic or anti-fibrotic roles by targeting genes collectively or respectively which involve in hepatic fibrosis related signaling pathways and hepatic stellate cell activation. Thus, good understandings of molecular mechanisms which are based on miRNA families may provide new ideas for the molecular targeted therapy of hepatic fibrosis in the future.

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“…Studies have shown that HBV and its viral proteins are at least partially responsible for over-activation of TGF-β signaling in HBV-related HCC [13, 14]. Lee et al found that HBx enhanced phosphorylation of pSmad2/3C by binding with Smad4 and amplified TGF-β signal pathway in several HCC cell lines, which led to the enhanced transcriptional activation of TGF-β-responsive genes [15].…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a

Liu

et al. 2016

Oncotarget

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Over-activation of transforming growth factor-β (TGF-β) signaling pathway promotes cell migration and invasion in hepatocellular carcinoma (HCC). The Hepatitis B virus X protein (HBx) is involved in the enhancement of TGF-β signaling pathway in HCC while the mechanism remains unclear. Protein phosphatase magnesium dependent 1A (PPM1a) functions as a phosphatase essential for terminating the TGF-β signaling pathway by dephosphorylating p-Smad2/3. In this study, we found that HBx dose-dependently downregulated PPM1a protein level in the presence of TGF-β, while having no effect on its mRNA level. Further study showed that HBx increased the ubiquitination of PPM1a and accelerated its proteasomal degradation. Restoration of PPM1a almost completely abrogated HBx mediated promotion on HCC migration and invasion. This involvement of PPM1a in HBx-related HCC was further confirmed with immunohistochemical analysis in HCC tissue. Compared with paired pericarcinous tissue, HCC tissue showed decreased PPM1a level. Besides, PPM1a level is negatively correlated with HBx expression. Taken together, our present study suggests that HBx-induced degradation of PPM1a is a novel mechanism for over-activation of TGF-β pathway in HCC development, which might provide potential candidates for clinical diagnosis and treatment.

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Hepatitis B Virus Regulates Apoptosis and Tumorigenesis through the MicroRNA-15a-Smad7-Transforming Growth Factor Beta Pathway

Cited by 47 publications

References 39 publications

Hepatitis B Virus–Upregulated LNC‐HUR1 Promotes Cell Proliferation and Tumorigenesis by Blocking p53 Activity

Hepatitis B Virus–Upregulated LNC‐HUR1 Promotes Cell Proliferation and Tumorigenesis by Blocking p53 Activity

The roles of microRNA families in hepatic fibrosis

Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a

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