IMMUNE NETWORK

  • 제21권5호
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  • Pages.37.1-37.17
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  • 2021
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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Hepatitis B virus X Protein Promotes Liver Cancer Progression through Autophagy Induction in Response to TLR4 Stimulation

  • Juhee Son (Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine) ;
  • Mi-Jeong Kim (Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine) ;
  • Ji Su Lee (Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine) ;
  • Ji Young Kim (Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine) ;
  • Eunyoung Chun (CHA Vaccine Institute) ;
  • Ki-Young Lee (Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine)
  • 투고 : 2021.08.27
  • 심사 : 2021.10.20
  • 발행 : 2021.10.31
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초록

Hepatitis B virus X (HBx) protein has been reported as a key protein regulating the pathogenesis of HBV-induced hepatocellular carcinoma (HCC). Recent evidence has shown that HBx is implicated in the activation of autophagy in hepatic cells. Nevertheless, the precise molecular and cellular mechanism by which HBx induces autophagy is still controversial. Herein, we investigated the molecular and cellular mechanism by which HBx is involved in the TRAF6-BECN1-Bcl-2 signaling for the regulation of autophagy in response to TLR4 stimulation, therefore influencing the HCC progression. HBx interacts with BECN1 (Beclin 1) and inhibits the association of the BECN1-Bcl-2 complex, which is known to prevent the assembly of the pre-autophagosomal structure. Furthermore, HBx enhances the interaction between VPS34 and TRAF6-BECN1 complex, increases the ubiquitination of BECN1, and subsequently enhances autophagy induction in response to LPS stimulation. To verify the functional role of HBx in liver cancer progression, we utilized different HCC cell lines, HepG2, SK-Hep-1, and SNU-761. HBx-expressing HepG2 cells exhibited enhanced cell migration, invasion, and cell mobility in response to LPS stimulation compared to those of control HepG2 cells. These results were consistently observed in HBx-expressed SK-Hep-1 and HBx-expressed SNU-761 cells. Taken together, our findings suggest that HBx positively regulates the induction of autophagy through the inhibition of the BECN1-Bcl-2 complex and enhancement of the TRAF6-BECN1-VPS34 complex, leading to enhance liver cancer migration and invasion.

키워드

과제정보

This work was supported by the National Research Foundation of Korea (NRF) Grants funded by the Korean Government (NRF-2021R1F1A1049324, NRF-2021R1A2C1094478), Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Education (2020R1A6C101A191), Ministry of Science ICT and Future Planning (MSIP) funded by the Korean Government (NRF-2016R1A5A2945889).

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