Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul 05029, Korea.
Int J Mol Sci. 2020 Jan 31;21(3):948. doi: 10.3390/ijms21030948.
Hepatitis B virus (HBV) infection is a major factor in the development of various liver diseases such as hepatocellular carcinoma (HCC). Among HBV encoded proteins, HBV X protein (HBx) is known to play a key role in the 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 the ERK signaling pathway. Our data show that HNF4α was suppressed during long-term HBV infection in cultured HepG2-NTCP cells as well as in a 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 provide proof of the effect of HBV infection in manipulating the HNF4α regulatory pathway in HCC development.
乙型肝炎病毒（HBV）感染是导致各种肝脏疾病（如肝癌）的主要因素。在 HBV 编码的蛋白质中，HBV X 蛋白（HBx）被认为在肝癌的发生发展中起着关键作用。肝细胞核因子 4α（HNF4α）是一种核转录因子，对肝细胞分化至关重要。然而，HBV 感染中 HNF4α 的表达水平及其调控机制尚不清楚。在这里，我们观察到在稳定表达 HBV 全基因组或 HBx 蛋白的细胞中 HNF4α 的抑制，而瞬时转染 HBV 复制子或 HBx 质粒对 HNF4α 水平没有影响。重要的是，在稳定表达 HBV 或 HBx 的肝细胞中，通过抑制 ERK 信号通路可以恢复下调的 HNF4α 水平。我们的数据表明，在培养的 HepG2-NTCP 细胞中以及在经 pAAV-HBV hydrodynamic 注射或经 rAAV-HBV 静脉感染的小鼠模型中，HBV 感染会抑制 HNF4α。重要的是，HNF4α 的下调增加了细胞增殖，这有助于异种移植裸鼠肿瘤的形成和发展。这里呈现的数据证明了 HBV 感染在操纵 HCC 发展中 HNF4α 调控途径方面的作用。
