Obesity synergizes with HBx, Src and p53 mutation accelerate hepatocarcinogenesis [Microarray]
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ABSTRACT: Previous studies have identified liver cancer associated to NASH, diabetes, obesity, and some genetic risk factors. We want to investigate the synergism between diet and genetic risk factors in hepatocarcinogenesis using omics data of four background zebrafish in three types of diet. We found the fishes have more genetic risk factors at the same time, and have higher probability to accelerate cancer formation. Overfed and high fat diet will increase the chance. Moreover, the results showed metabolism and genetic information processing, including the pathways of fatty acid metabolism, steroid biosynthesis and ribosome biogenesis are highly affected in hepatocellular carcinoma.
Project description:Previous studies have identified liver cancer associated to NASH, diabetes, obesity, and some genetic risk factors. We want to investigate the synergism between diet and genetic risk factors in hepatocarcinogenesis using omics data of four background zebrafish in three types of diet. We found the fishes have more genetic risk factors at the same time, and have higher probability to accelerate cancer formation. Overfed and high fat diet will increase the chance. Moreover, the results showed metabolism and genetic information processing, including the pathways of fatty acid metabolism, steroid biosynthesis and ribosome biogenesis are highly affected in hepatocellular carcinoma.
Project description:Hepatocarcinogenesis is a multistep process that starts from fatty liver and transitions to fibrosis and, finally, into cancer. Many etiological factors, including hepatitis B virus X antigen (HBx) and p53 mutations, have been implicated in hepatocarcinogenesis. However, potential synergistic effects between these two factors and the underlying mechanisms by which they promote hepatocarcinogenesis are still unclear. In this report, we show that the synergistic action of HBx and p53 mutation triggers progressive hepatocellular carcinoma (HCC) formation via src activation in zebrafish. Liver-specific expression of HBx in wild-type zebrafish caused steatosis, fibrosis and glycogen accumulation. However, the induction of tumorigenesis by HBx was only observed in p53 mutant fish and occurred in association with the up-regulation and activation of the src tyrosine kinase pathway. Furthermore, the overexpression of src in p53 mutant zebrafish also caused hyperplasia, HCC, and sarcomatoid HCC, which were accompanied by increased levels of the signaling proteins p-erk, p-akt, myc, jnk1 and vegf. Increased expression levels of lipogenic factors and the genes involved in lipid metabolism and glycogen storage were detected during the early stages of hepatocarcinogenesis in the HBx and src transgenic zebrafish. The up-regulation of genes involved in cell cycle regulation, tumor progression and other molecular hallmarks of human liver cancer were found at later stages in both HBx and src transgenic, p53 mutant zebrafish. Together, our study demonstrates that HBx and src overexpression induced hepatocarcinogenesis in p53 mutant zebrafish. This phenomenon mimics human HCC formation and provides potential in vivo platforms for drug screening for therapies for human liver cancer.
Project description: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.
Project description:Expression microarray of livers from adult zebrafish: control, overfed, and ahcy+/- Comparison of expression from livers obtained from ahcy+/+, overfed ahcy+/+, ahcy+/- control and ahcy+/- overfed. Adult zebrafish, ahcy+/+ and +/-, were given a regular diet or were overfed for a month. Livers were removed, RNA isolated, and expression microarray was performed.
Project description:Nutritional and genetic risk factors for intestinal tumors are additive on mouse tumor phenotypes, demonstrating that diet and genetic factors impact risk by distinct combinatorial mechanisms. We analyzed expression profiles of small intestine crypts and villi from mice with nutritional and genetic risk factors. The results advanced our understanding of the mechanistic roles played by major risk factors in the pathogenesis of intestinal tumors. Small intestine crypts and villi from mice with nutritional (Ain76A, NWD1, and NWD2) and genetic risk factors (WT, Apc1638N/+ and p21-/-) were collected for RNA extraction and analysis using the Affymetrix 3' IVT expression microarray. Three or four replicates per tissue/risk factor.
Project description:Nutritional and genetic risk factors for intestinal tumors are additive on mouse tumor phenotypes, demonstrating that diet and genetic factors impact risk by distinct combinatorial mechanisms. We analyzed expression profiles of small intestine crypts and villi from mice with nutritional and genetic risk factors. The results advanced our understanding of the mechanistic roles played by major risk factors in the pathogenesis of intestinal tumors.