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  2. College of Bioresources and Agriculture / 生物資源暨農學院
  3. School of Veterinary Medicine / 獸醫專業學院
  4. Molecular and Comparative Pathobiology / 分子暨比較病理生物學研究所
  5. Liver-Specific Expressions of HBx and src in the p53 Mutant Trigger Hepatocarcinogenesis in Zebrafish
 
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Liver-Specific Expressions of HBx and src in the p53 Mutant Trigger Hepatocarcinogenesis in Zebrafish

Journal
PLoS ONE
Journal Volume
8
Journal Issue
10
Date Issued
2013
Author(s)
Lu, J.-W.
Yang, W.-Y.
Tsai, S.-M.
Lin, Y.-M.
PEN-HENG CHANG  
Chen, J.-R.
Wang, H.-D.
Wu, J.-L.
Jin, S.-L.C.
Yuh, C.-H.
DOI
10.1371/journal.pone.0076951
URI
http://www.scopus.com/inward/record.url?eid=2-s2.0-84885123381&partnerID=MN8TOARS
http://scholars.lib.ntu.edu.tw/handle/123456789/377339
Abstract
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. ? 2013 Lu et al.
SDGs

[SDGs]SDG3

Other Subjects
glycogen; hepatitis B virus X antigen; mitogen activated protein kinase; Myc protein; protein kinase B; protein p53; protein tyrosine kinase; stress activated protein kinase 1; unclassified drug; vasculotropin; virus antigen; animal experiment; animal model; animal tissue; article; cancer growth; cancer staging; controlled study; drug screening; enzyme activation; enzyme phosphorylation; gene function; gene mutation; glycogen metabolism; in vivo study; lipid metabolism; lipogenesis; liver carcinogenesis; liver cell carcinoma; liver hyperplasia; nonhuman; protein analysis; protein expression; signal transduction; tissue specificity; transgenic animal; upregulation; zebra fish; Animals; Animals, Genetically Modified; Apoptosis; Carcinogenesis; Carcinoma, Hepatocellular; Cell Cycle; Enzyme Activation; Fibrosis; Gene Expression; Glycogen; Humans; Hyperplasia; Lipogenesis; Liver; Liver Neoplasms; Mutation; Neoplasm Metastasis; Organ Specificity; Proliferating Cell Nuclear Antigen; Recombinant Fusion Proteins; Signal Transduction; src-Family Kinases; Trans-Activators; Tumor Markers, Biological; Tumor Suppressor Protein p53; Zebrafish
Type
journal article

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