title: Inducible and repressable oncogene-addicted hepatocellular carcinoma in Tet-on xmrk transgenic zebrafish.
abstract: OBJECTIVE
  Liver cancer, mainly hepatocellular carcinoma, is a major malignancy and currently there are no effective treatment protocols due to insufficient understanding of hepatocarcinogenesis. As a potentially high-throughput and cost-effective experimental model, the zebrafish is increasingly recognized for disease studies. Here, we aim at using the zebrafish to generate a convenient hepatocellular carcinoma model.
  
  
  METHODS
  Using the Tet-on system for liver-specific expression of fish oncogene xmrk, a hyperactive version of epidermal growth factor receptor homolog, we have generated transgenic zebrafish with inducible development of liver cancer.
  
  
  RESULTS
  Liver tumors were rapidly induced with 100% penetrance in both juvenile and adult xmrk transgenic fish. Histological examination indicated that they all showed features of hepatocellular carcinoma. The induced liver tumors regressed rapidly upon inducer withdrawal. During the tumor induction stage, we detected increased cell proliferation and activation of Xmrk downstream targets Erk and Stat5, which were important for liver tumorigenesis as proved by inhibition experiments. When tumors regressed, there were decreased phosphorylated Erk and Stat5 accompanied with an increase in apoptosis.
  
  
  CONCLUSIONS
  Our zebrafish model demonstrates the potential of a hyperactivated epidermal growth factor receptor pathway in initiating heptocarcinogenesis. It provides clear evidence for the requirement of only a single oncogene for HCC initiation and maintenance and is thus a convenient model for further investigation of oncogene addiction and future anti-cancer drug screening.
authors: Department of Biological Sciences, National University of Singapore, Singapore.
authors: Zhen
authors: Z
authors: Li
authors: Xiaoqian
authors: X
authors: Huang
authors: Huiqing
authors: H
authors: Zhan
authors: Zhiqiang
authors: Z
authors: Zeng
authors: Caixia
authors: C
authors: Li
authors: Jan M
authors: JM
authors: Spitsbergen
authors: Svenja
authors: S
authors: Meierjohann
authors: Manfred
authors: M
authors: Schartl
authors: Zhiyuan
authors: Z
authors: Gong
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage; D005260:Female; D029941:Fish Proteins / Q000235:genetics*; D015870:Gene Expression; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D009857:Oncogenes / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics*
chemical_list: D029941:Fish Proteins; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D020794:Receptor Protein-Tyrosine Kinases; C077101:Xmrk protein, Xiphophorus; D004318:Doxycycline