Omics-based Investigation of Diet-induced Obesity Synergized with HBx, Src, and p53 Mutation Accelerating Hepatocarcinogenesis in Zebrafish Model

Wan-Yu Yang,Sing-Han Huang,Jinn-Moon Yang,Chiou-Hwa Yuh,Yong-Chun Luo,Hua-Kuo Lin,Pei-Shu Rao

doi:10.3390/cancers11121899

Abstract

The primary type of liver cancer, hepatocellular carcinoma (HCC), has been associated with nonalcoholic steatohepatitis, diabetes, and obesity. Previous studies have identified some genetic risk factors, such as hepatitis B virus X antigens, overexpression of SRC oncogene, and mutation of the p53 tumor suppressor gene; however, the synergism between diet and genetic risk factors is still unclear. To investigate the synergism between diet and genetic risk factors in hepatocarcinogenesis, we used zebrafish with four genetic backgrounds and overfeeding or high-fat-diet-induced obesity with an omics-based expression of genes and histopathological changes. The results show that overfeeding and high-fat diet can induce obesity and nonalcoholic steatohepatitis in wild-type fish. In HBx, Src (p53-) triple transgenic zebrafish, diet-induced obesity accelerated HCC formation at five months of age and increased the cancer incidence threefold. We developed a global omics data analysis method to investigate genes, pathways, and biological systems based on microarray and next-generation sequencing (NGS, RNA-seq) omics data of zebrafish with four diet and genetic risk factors. The results show that two Kyoto Encyclopedia of Genes and Genomes (KEGG) systems, metabolism and genetic information processing, as well as the pathways of fatty acid metabolism, steroid biosynthesis, and ribosome biogenesis, are activated during hepatocarcinogenesis. This study provides a systematic view of the synergism between genetic and diet factors in the dynamic liver cancer formation process, and indicate that overfeeding or a high-fat diet and the risk genes have a synergistic effect in causing liver cancer by affecting fatty acid metabolism and ribosome biogenesis.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of mortality worldwide [1,2], and there is still no effective therapy available due to its heterogeneity [3].Major risk factors for hepatocellular carcinoma (HCC) include hepatitis B and hepatitis C virus infection, and aflatoxin contamination, as well as chronic alcohol consumption
When compared to WT with a normal diet, DIO or fat diet (FAT) increased the expression of lipogenic factors and lipogenic enzymes, including 1-acylglycerol-3-phosphate acyltransferase, fatty acid synthase, and phosphatidate phosphatase using Quantitative PCR (qPCR) (Figure 1C) and hematoxylin and eosin (H&E) (Figure 1D)
Against a normal genetic background, diet-induced obesity will increase the chance of fatty liver with a low incidence of hyperplasia

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of mortality worldwide [1,2], and there is still no effective therapy available due to its heterogeneity [3]. Major risk factors for HCC include hepatitis B and hepatitis C virus infection, and aflatoxin contamination, as well as chronic alcohol consumption. HCC may be formed through hepatitis, fatty liver, and liver fibrosis, and eventually, develop into liver cancer. Hepatitis B (HBV) infection is a major risk factor of HCC [4], and X antigen (HBx) has been reported to be the most obvious carcinogen-induced liver cancer in mice [5] and zebrafish [6]. In the HBx-induced HCC mouse model, SRC was identified as a common regulator [9]

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Discussion

Conclusion