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

You

et al. 2019

Virol J

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Background The ubiquitin proteasome system (UPS) regulates the expression levels of cellular proteins by ubiquitination of protein substrates followed by their degradation via the proteasome. As a highly conserved cellular degradation mechanism, the UPS affects a variety of biological processes and participates in viral propagation. Main body During hepatitis B virus (HBV) infection, the UPS is shown to act as a double-edged sword in viral pathogenesis. On the one hand, the UPS acts as a host defense mechanism to selectively recognize HBV proteins as well as special cellular proteins that favor the viral life cycle and induces their ubiquitin-dependent proteasomal degradation to limit HBV infection. On the other hand, the HBV has evolved to subvert the UPS function for its own advantage. Moreover, in the infected hepatocytes, certain cellular proteins that are dependent on the UPS are involved in abnormal biological processes which are mediated by HBV. Conclusion The molecular interaction of HBV with the UPS to modulate viral propagation and pathogenesis is summarized in the review. Considering the important role of the UPS in HBV infection, a better understanding of the HBV-UPS interaction could provide novel insight into the mechanisms that are involved in viral replication and pathogenesis and help to develop potential treatment strategies targeting the UPS.

Section: Main Textmentioning

confidence: 99%

The interaction of hepatitis B virus with the ubiquitin proteasome system in viral replication and associated pathogenesis

You

et al. 2019

Virol J

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“…HBV possesses four overlapping open reading frames, namely C, P, S and X (24–26). The coding protein HBX was reported to possess multiple transcriptional regulatory activities (2,30,31). The present study explored whether HBX alone could facilitate AP1M1 expression.…”

Section: Resultsmentioning

confidence: 99%

“…Although previous studies have demonstrated that HBV infection can increase the risk of liver cancer, the exact molecular mechanism of this process remains undiscovered (1,2,5,6). In the present study, it was demonstrated that AP1M1 acted as a cancer-promoting factor.…”

Section: Discussionmentioning

confidence: 99%

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HBV upregulates AP‑1 complex subunit mu‑1 expression via the JNK pathway to promote proliferation of liver cancer cells

et al. 2019

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Although hepatitis B virus (HBV) infection is responsible for liver cancer, the exact mechanism of its action remains unclear. μ1 adaptin is an intrinsic part of the clathrin adaptor AP-1 complex. In addition to its canonical biological function that involves cargo sorting and vesicular transport, recent studies have demonstrated that μ1 adaptin participates in cell growth and proliferation. The aim of the present study was to investigate the effects of the clathrin adaptor AP-1 complex subunit mu-1 (AP1M1) on liver cancer cell proliferation. The present study reports for the first time that AP1M1 is upregulated in the HBV-transfected HepG2.215 liver cancer cells. Silencing of AP1M1 in HepG2.215 cells suppressed their proliferation, while the overexpression of AP1M1 in HepG2 cells promoted cell proliferation. The data suggested that AP1M1 is one of the crucial factors involved in the progression of liver cancer caused by HBV infection. In addition, it was demonstrated that HBV facilitated AP1M1 expression in a JNK-dependent manner. The increased expression levels of AP1M1 enhanced phosphorylation of protein kinase B and accelerated cell proliferation. Unraveling the effects of AP1M1 on liver cancer cell proliferation and the mechanism of AP1M1 transcriptional regulation may provide new therapeutic targets for HBV-positive liver cancer.

“…Epithelial-mesenchymal transition (EMT) is a significant event in the development of HBV-associated HCC [ 7 ]. HBX has been reported to induce the EMT phenotype in hepatoma cells [ 8 – 11 ], with the decreased levels of epithelial cell–cell adhesion molecule E-cadherin, while the increased expressions of cytoskeletal actin component β-catenin and vimentin. Moreover, HBX can regulate the expression of E-cadherin and β-catenin with multiple molecular mechanisms [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein promotes vimentin expression via LIM and SH3 domain protein 1 to facilitate epithelial-mesenchymal transition and hepatocarcinogenesis

You

Yuan

et al. 2021

Cell Commun Signal

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Background Hepatitis B virus (HBV) X protein (HBX) has been reported to be responsible for the epithelial-mesenchymal transition (EMT) in HBV-related hepatocellular carcinoma (HCC). Vimentin is an EMT-related molecular marker. However, the importance of vimentin in the pathogenesis of HCC mediated by HBX has not been well determined. Methods The expression of vimentin induced by HBX, and the role of LIM and SH3 domain protein 1 (LASP1) in HBX-induced vimentin expression in hepatoma cells were examined by western blot and immunohistochemistry analysis. Both the signal pathways involved in the expression of vimentin, the interaction of HBX with vimentin and LASP1, and the stability of vimentin mediated by LASP1 in HBX-positive cells were assessed by western blot, Co-immunoprecipitation, and GST-pull down assay. The role of vimentin in EMT, proliferation, and migration of HCC cells mediated by HBX and LASP1 were explored with western blot, CCK-8 assay, plate clone formation assay, transwell assay, and wound healing assay. Results Vimentin expression was increased in both HBX-positive hepatoma cells and HBV-related HCC tissues, and the expression of vimentin was correlated with HBX in HBV-related HCC tissues. Functionally, vimentin was contributed to the EMT, proliferation, and migration of hepatoma cells mediated by HBX. The mechanistic analysis suggested that HBX was able to enhance the expression of vimentin through LASP1. On the one hand, PI3-K, ERK, and STAT3 signal pathways were involved in the upregulation of vimentin mediated by LASP1 in HBX-positive hepatoma cells. On the other hand, HBX could directly interact with vimentin and LASP1, and dependent on LASP1, HBX was capable of promoting the stability of vimentin via protecting it from ubiquitination mediated protein degradation. Besides these, vimentin was involved in the growth and migration of hepatoma cells mediated by LASP1 in HBX-positive hepatoma cells. Conclusion Taken together, these findings demonstrate that, dependent on LASP1, vimentin is crucial for HBX-mediated EMT and hepatocarcinogenesis, and may serve as a potential target for HBV-related HCC treatment.