Pathway analysis for gene expression profile in the Hepatitis B
Virus X protein induced Hepatocellular Carcinoma mouse model
Ting-Fen Tsai3, Pei-Ting Lin1, Yu-I Lin1, , Shih-Feng Tsai1, Shwu-Rong Grace Shieh2, Chiou-Hwa
Yuh1, 4, 5
1
Division of Molecular and Genomic Medicine, National Health Research Institutes, 2Institute of
Statistical Science, Academia Sinica, 3Faculty of Life Science and Institute of Genome Sciences,
Division of Molecular and Genomic Medicine, National Health Research Institutes, 4 Institute of
Bioinformatics and Structural Biology, National Tsing Hua University, 5 Department of the Biological
Science & Technology, National Chiao Tung University
Abstract
Hepatocellular carcinoma (HCC) is the number one leading cause of cancer-related deaths in
Taiwan. The HBx antigen in the Hepatitis B virus plays an important role in establishing the formation
of HCC. However, the detailed gene regulatory networks in Hepatocellular Carcinoma carcinogenesis
are not clear. A better understanding of the molecular pathogenesis of HBx induced HCC will provide
clues for more effective preventive and therapeutic strategy.
We establish the carcinogenesis pathway by using HBx induced HCC transgenic mice model,
developed in Dr. Tsai Ting-Fang’s group. We collaborate with Dr. Shieh Shwu-Rong at Academia
Sinica using statistics to capture genes that have similar trend. Thus, we identified a group of genes
which are increasing expressing during the course of carcinogenesis. We also identified a group of genes
which are decreasing expressing from early to late stage. Furthermore, we classify the genes which have
differential expression between tumor and non-tumor samples. These genes may be related to disease
progress. The relevant pathways were analyzed using Pathway Studio software. We found many
pathways are activated throughout the different stages. Some key genes were activated as early as 1.5
month in many pathways. Some other genes in the same pathway are turned on at 8 months and 12
months. Eventually at 14 to 16 months, many pathways are activated and the cancer formed. Through
our study, many genes are activated during the carcinogenesis, in a continuously activation and tumor
specific manner. The most important carcinogenesis pathways include Erk-PI3K, EGFR signal pathway,
F2R signaling pathway, and GRM1/5 -> CREB1 signaling pathway etc. The known genes (pathways)
are about 10% of genes of what we found, that indicates the majority of genes might serve as new cancer
biomarkers.
The systematic approaches in this project provide the fundamental basis for the HCC
carcinogenesis. We identify some of the biomarkers as well as the pathways and networks underlying
HCC formation. It can make clear the role of HBx induced HCC at the early, middle, and late stages, in
order to predict and prevent the development of cancer. The results will also help elucidate the
possibility for utilization of those biomarkers as a molecular target for the treatment of human HCC.
Keywords: Hepatocellular carcinoma, HBV X transgenic mice, genomic instability,
methylation, proteomic, DNA microarray