Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Suppression of Hepatocyte Nuclear Factor 4 Alpha by Long-Term Infection of Hepatitis B Virus Contributes to Tumor Cell Proliferation

Version 1 : Received: 24 January 2020 / Approved: 25 January 2020 / Online: 25 January 2020 (15:25:57 CET)

A peer-reviewed article of this Preprint also exists.

Park, S.; Ha, Y.N.; Dezhbord, M.; Lee, A.R.; Park, E.-S.; Park, Y.K.; Won, J.; Kim, N.Y.; Choo, S.Y.; Shin, J.J.; Ahn, C.H.; Kim, K.-H. Suppression of Hepatocyte Nuclear Factor 4 α by Long-term Infection of Hepatitis B Virus Contributes to Tumor Cell Proliferation. Int. J. Mol. Sci. 2020, 21, 948. Park, S.; Ha, Y.N.; Dezhbord, M.; Lee, A.R.; Park, E.-S.; Park, Y.K.; Won, J.; Kim, N.Y.; Choo, S.Y.; Shin, J.J.; Ahn, C.H.; Kim, K.-H. Suppression of Hepatocyte Nuclear Factor 4 α by Long-term Infection of Hepatitis B Virus Contributes to Tumor Cell Proliferation. Int. J. Mol. Sci. 2020, 21, 948.

Journal reference: Int. J. Mol. Sci. 2020, 21, 948
DOI: 10.3390/ijms21030948

Abstract

Hepatitis B virus (HBV) infection is a major factor in development of various liver diseases such as hepatocellular carcinoma (HCC). Among HBV encoded proteins, HBV X protein (HBx) is known to play key role in development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear transcription factor which is critical for hepatocyte differentiation. However, the expression level as well as its regulatory mechanism in HBV infection have yet to be clarified. Here, we observed the suppression of HNF4α in cells which stably express HBV whole genome or HBx protein alone, while transient transfection of HBV replicon or HBx plasmid had no effect on the HNF4α level. Importantly, in the stable HBV- or HBx-expressing hepatocytes, the downregulated level of HNF4α was restored by inhibiting ERK signaling pathway. Our data showed that HNF4α was suppressed during long-term HBV infection in cultured HepG2-NTCP cells as well as in mouse model following hydrodynamic injection of pAAV-HBV or in mice intravenously infected with rAAV-HBV. Importantly, HNF4α downregulation increased cell proliferation which contributed to the formation and development of tumor in xenograft nude mice. The data presented here provided several proofs for the effect of HBV infection in manipulating HNF4α regulatory pathway in HCC development.

Subject Areas

Hepatitis B virus; hepatocyte nuclear factor 4 alpha; long-term infection; ERK signaling pathway

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