The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice

Abstract

Hepatitis C virus (HCV) is the main cause of chronic hepatitis worldwide. Chronic hepatitis ultimately results in the development of hepatocellular carcinoma (HCC). However, the mechanism of hepatocarcinogenesis in chronic HCV infection is still unclear. The ability of the core protein of HCV to modulate gene transcription, cell proliferation and cell death may be involved in the pathogenesis of HCC. Here, we report the development of HCC in two independent lines of mice transgenic for the HCV core gene, which develop hepatic steatosis early in life as a histological feature characteristic of chronic hepatitis C. After the age of 16 months, mice of both lines developed hepatic tumors that first appeared as adenomas containing fat droplets in the cytoplasm. Then HCC, a more poorly-differentiated neoplasia, developed from within the adenomas, presenting in a 'nodule-in-nodule' manner without cytoplasmic fat droplets; this closely resembled the histopathological characteristics of the early stage of HCC in patients with chronic hepatitis C. These results indicate that the HCV core protein has a chief role in the development of HCC, and that these transgenic mice provide good animal models for determining the molecular events in hepatocarcinogenesis with HCV infection.

Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein†

“…The core protein binds to cellular proteins, suppresses or enhances apoptosis, and modulates the transcription of some host genes. 1 In addition, transgenic mice expressing the core protein develop HCC, [2][3][4] indicating a direct contribution of the core protein to the pathogenesis of hepatitis C.…”

A zebrafish model of intrahepatic cholangiocarcinoma by dual expression of hepatitis B virus X and hepatitis C virus core protein in liver

“…From the 1 Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan; 2 Department of Pathology, Chang Gung Memorial Hospital, Keelung, Taiwan; 3 College of Medicine, Chang Gung Univeristy, Taoyuan, Taiwan; 4 Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan; 5 Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan; 6 Institute of Microbiology and Biochemistry, National Taiwan University, Taipei, Taiwan; 7 Department of Aquaculture, and Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan; 8 Division of Molecular and Developmental Biology, National Institute of Genetics, and Department of Genetics, Graduate University for Advanced Studies (SOKENDAI), Mishima, Shizuoka, Japan.…”

“…The HCV core protein (HCP) consists of 192 amino acids and modulates multiple cellular processes, including oncogenesis. 5 Hepatitis B virus (HBV) infection is a global health problem that afflicts more than 350 million people. Although HBV specifically infects hepatocytes, 6 HBV has recently been considered a risk factor for ICC.…”

IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity?

“…The HCV core protein is implicated in disease pathogenesis, influencing several cellular pathways, including oxidative stress, cell proliferation, and steatosis, and exhibiting oncogenic potential in transgenic models [7]. Among other regions of the HCV genome, variations in the core sequence have been linked to disease progression and HCC risk in patients affected by genotype-1 HCV, which is the most common and difficult to cure viral strain.…”

“…Indeed, promotion of liver fat accumulation and the resultant inflammation, altered iron metabolism/oxidative stress, and insulin resistance are involved in the hepatocarcinogenesis promoted by the HCV core [7,[26][27][28], but systematic data on the relationship between HCV core variants and steatosis are not available.…”