High load hepatitis B virus replication inhibits hepatocellular carcinoma cell metastasis through regulation of epithelial–mesenchymal transition

Wang, Tianzhen; Jin, Yinji; Zhao, Ruihua; Wu, Yiqi; Zhang, Yuhua; Wu, Di; Kong, Dan; Jin, Xiaoming; Zhang, Fengmin

doi:10.1016/j.ijid.2013.11.015

Cited by 10 publications

(4 citation statements)

References 32 publications

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“…A study of the HepG2 and HUH-7 cell lines also suggested that HBx directly upregulates expression of the bHLH transcription factor E12/E47, inhibits E-cadherin expression, and induces the process of EMT [ 115 , 116 ]. In contrast, Wang et al [ 117 ] demonstrated that EMT was suppressed in the HepG2.2.15 cell line in the presence of high levels of HBV virus replication. However, the underlying mechanism is still unclear, and moreover, the effect of virus on EMT in liver cancer may not be dependent only on HBx levels, an issue which requires further investigation.…”

Section: Introductionmentioning

confidence: 96%

Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma

Long

Dai

2018

J Exp Clin Cancer Res

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Epithelial-to-mesenchymal transition (EMT) is a complex process involving multiple genes, steps and stages. It refers to the disruption of tight intercellular junctions among epithelial cells under specific conditions, resulting in loss of the original polarity, order and consistency of the cells. Following EMT, the cells show interstitial cell characteristics with the capacity for adhesion and migration, while apoptosis is inhibited. This process is critically involved in embryogenesis, wound-healing, tumor invasion and metastasis. The tumor microenvironment is composed of infiltrating inflammatory cells, stromal cells and the active medium secreted by interstitial cells. Most patients with hepatocellular carcinoma (HCC) have a history of hepatitis virus infection. In such cases, major components of the tumor microenvironment include inflammatory cells, inflammatory factors and virus-encoded protein are major components. Here, we review the relationship between EMT and the inflammatory tumor microenvironment in the context of HCC. We also further elaborate the significant influence of infiltrating inflammatory cells and inflammatory mediators as well as the products expressed by the infecting virus in the tumor microenvironment on the EMT process.

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Section: Introductionmentioning

confidence: 96%

Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma

Long

Dai

2018

J Exp Clin Cancer Res

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“…However, contrary to these reports, we have shown that the expression of E-cadherin was upregulated in cells that transiently or stably expressed HBV (Fig 1). Additionally, Wang et al also reported that E-cadherin expression was downregulated following inhibition of HBV replication via silenced by siRNAs in HepG2.2.15 cells [19]. Similar contradictory results have been reported in HCV infection cell models [20].…”

Section: Discussionmentioning

confidence: 59%

E-cadherin binds glycosylated sodium-taurocholate cotransporting polypeptide to facilitate hepatitis B virus entry

Zhang

Duan

et al. 2019

Preprint

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35Hepatitis B virus (HBV) continues to pose a serious public health risk and is one 36 of the major causes of chronic liver disease and hepatocellular carcinoma. Current 37 antiviral therapy does not effectively eradicate HBV and, thus, further investigation 38 into the mechanisms employed by HBV to allow for invasion of host cells, is critical 39 for the development of novel therapeutic agents. Sodium-taurocholate cotransporting 40 polypeptide (NTCP) has been identified as a functional receptor for HBV. However, 41 the specific mechanism by which HBV and NTCP interact remains unclear. Herein 42 we show that the expression of E-cadherin was upregulated in cells expressing HBV, 43 while knockdown of E-cadherin in HepG2-NTCP cells, HepaRG cells and primary 44 human hepatocytes served to significantly inhibit infection by HBV and HBV 45 pseudotyped particles. Alternatively, exogenous E-cadherin expression was found to 46 significantly enhance HBV uptake by HepaRG cells. Further, mechanistic studies 47 identified glycosylated NTCP localized to the cell membrane via E-cadherin binding, 48 which subsequently allowed for more efficient binding between NTCP and the preS1 49 of the large HBV surface proteins. E-cadherin was also found to play a key role in 50 establishing and maintaining hepatocyte polarity, which is essential for efficient HBV 51 infection. These observations suggest that E-cadherin facilitates HBV entry through 52 regulation of NTCP distribution and hepatocyte polarity. 53 54 Author Summary 55 Hepatitis B Virus (HBV) still seriously endangers public health. It is very 3 56important to understand the mechanism of HBV invading host cells for developing 57 new therapy target. Sodium-taurocholate cotransporting polypeptide (NTCP) is the 58 key receptor mediating HBV invasion, while other molecules also exhibit important 59 roles in ensuring efficient and productive HBV infection. This study reports that 60 E-cadherin facilitates HBV entry by directly interacting with glycosylated NTCP to 61 mediate its distribution on the hepatocyte membrane and also affects the efficacy of 62 HBV invasion by influncing hepatocyte polarity. 63 64 Introduction 65 Hepatitis B virus (HBV), a member of the Hepadnaviridae family, is a small, 66 enveloped DNA virus [1] that infects human liver parenchymal cells. Although the 67 widespread use of vaccines has greatly reduced the rate of infection, HBV continues 68 to pose a serious threat to global health, affecting more than 350 million individuals 69 worldwide, all of whom are at increased risk of developing liver cirrhosis and 70 hepatocellular carcinoma (HCC) [2]. Current therapeutic regimens that employ 71 direct-acting antivirals, with or without ribavirin, have significantly increased the 72 prevalence of escape mutants and cause serious adverse effects, thus, eliciting a low 73 curative rate in HBV patients [3].74 Furthermore, the lack of effective therapeutic options for HBV is partially due to 75 our incomplete understanding of the HBV life cycle, including the sta...

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“…Furthermore, the expression levels of vimentin are also increased in poorly differentiated HCC tissue samples (26,27). Whilst a high load of HBV replication inhibits the EMT of HCC cells (28), HBx is considered to contribute to the promotion of EMT. HBx may be able to induce an EMT phenotype in hepatoma cells, with decreased E-cadherin expression levels as well as an upregulation of vimentin and N-cadherin (29).…”

Section: The Proteins Associated With the Cytoskeleton That Are Deregmentioning

confidence: 99%

The regulation of proteins associated with the cytoskeleton by hepatitis B virus X protein during hepatocarcinogenesis

et al. 2017

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Abstract. Hepatocellular carcinoma (HCC) is a major malignant disease worldwide, and chronic hepatitis B virus (HBV) infection is one of the primary causes for this type of cancer. Hepatitis B virus X protein (HBx) is a non-structural protein encoded by the viral genome that has significant effects on the pathogenesis of HCC. With the development of high-throughput assays and technologies, the abnormal HBx-induced expression of certain cellular proteins with assorted biological functions has been investigated. These target proteins identified by various methods include specific proteins associated with the cellular cytoskeleton, which contribute to HBx-induced hepatocarcinogenesis. In addition, the cytoskeletal proteins deregulated by HBx are involved in cell morphogenesis, adhesion, migration and proliferation. This review aims to summarize the current understanding of the expression profiles of HBx-associated cytoskeletal proteins, as well as their complex functions and underlying mechanisms in hepatocarcinogenesis. Considering that the potential therapeutics for various types of tumors may function through the stabilization of cytoskeletal proteins in order to restrict cellular movement and limit intracellular processes, clarifying the mechanisms underlying protein-associated cytoskeleton dysregulation by HBx may provide novel possibilities and potent therapeutic targets for HBV-associated HCC. Contents

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High load hepatitis B virus replication inhibits hepatocellular carcinoma cell metastasis through regulation of epithelial–mesenchymal transition

Abstract: siRNAs were able to effectively inhibit HBV replication in vitro. A high load of HBV replication may inhibit the invasion and metastatic ability of HCC cells by reversing the EMT process.

Cited by 10 publications

References 32 publications

Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma

Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma

E-cadherin binds glycosylated sodium-taurocholate cotransporting polypeptide to facilitate hepatitis B virus entry

The regulation of proteins associated with the cytoskeleton by hepatitis B virus X protein during hepatocarcinogenesis

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