Identification of the common regulators for hepatocellular carcinoma induced by hepatitis B virus X antigen in a mouse model.
Hepatitis B virus X antigen plays an important role in the development of human hepatocellular carcinoma (HCC). The key regulators controlling the temporal downstream gene expression for HCC progression remains unknown. In this study, we took advantage of systems biology approach and analyzed the microarray data of the HBx transgenic mouse as a screening process to identify the differentially expressed genes and applied the software Pathway Studio to identify potential pathways and regulators involved in HCC. Using subnetwork enrichment analysis, we identified five common regulator genes: EDN1, BMP7, BMP4, SPIB and SRC. Upregulation of the common regulators was validated in the other independent HBx transgenic mouse lines. Furthermore, we verified the correlation of their RNA expression levels by using the human HCC samples, and their protein levels by using the human liver disease tissue arrays. EDN1, bone morphogenetic protein (BMP) 4 and BMP7 were upregulated in cirrhosis, BMP4, BMP7 and SRC were further upregulated in hepatocellular or cholangiocellular carcinoma samples. The trend of increasing expression of the common regulators correlates well with the progression of human liver cancer. Overexpression of the common regulators increases the cell viability, promotes migration and invasiveness and enhances the colony formation ability in Hep3B cells. Our approach allows us to identify the critical genes in hepatocarcinogenesis in an HBx-induced mouse model. The validation of the gene expressions in the liver cancer of human patients and their cellular function assays suggests that the identified common regulators may serve as useful molecular targets for the early-stage diagnosis or therapy for HCC.
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan.
Jeng-Wei
JW
Lu
Yu
Y
Hsia
Wan-Yu
WY
Yang
Yu-I
YI
Lin
Chao-Chin
CC
Li
Ting-Fen
TF
Tsai
Ko-Wei
KW
Chang
Grace S
GS
Shieh
Shih-Feng
SF
Tsai
Horng-Dar
HD
Wang
Chiou-Hwa
CH
Yuh
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins; D019061:src-Family Kinases / Q000235:genetics
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D004268:DNA-Binding Proteins; C423918:Spic protein, mouse; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C525820:bmp7 protein, mouse; C057628:hepatitis B virus X protein; D019061:src-Family Kinases