title: Chemical inhibition reveals differential requirements of signaling pathways in krasV12- and Myc-induced liver tumors in transgenic zebrafish.
abstract: Previously we have generated inducible liver tumor models by transgenic expression of an oncogene and robust tumorigenesis can be rapidly induced by activation of the oncogene in both juvenile and adult fish. In the present study, we aimed at chemical intervention of tumorigenesis for understanding molecular pathways of tumorigenesis and for potential development of a chemical screening tool for anti-cancer drug discovery. Thus, we evaluated the roles of several major signaling pathways in krasV12- or Myc-induced liver tumors by using several small molecule inhibitors: SU5402 and SU6668 for VEGF/FGF signaling; IWR1 and cardionogen 1 for Wnt signaling; and cyclopamine and Gant61 for Hedgehog signaling. Inhibition of VEGF/FGF signaling was found to deter both Myc- and krasV12-induced liver tumorigenesis while suppression of Wnt signaling relaxed only Myc- but not krasV12-induced liver tumorigenesis. Inhibiting Hedgehog signaling did not suppress either krasV12or Myc-induced tumors. The suppression of liver tumorigenesis was accompanied with a decrease of cell proliferation, increase of apoptosis, distorted liver histology. Collectively, our observations suggested the requirement of VEGF/FGF signaling but not the hedgehog signaling in liver tumorigenesis in both transgenic fry. However, Wnt signaling appeared to be required for liver tumorigenesis only in Myc but not krasV12transgenic zebrafish.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.|National University of Singapore graduate school for integrative sciences and engineering, National University of Singapore, Singapore.
authors.forename: Chuan
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: Qiqi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: Hankun
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.|National University of Singapore graduate school for integrative sciences and engineering, National University of Singapore, Singapore.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Gong
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors*; D016259:Genes, myc; D008113:Liver Neoplasms / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D005346:Fibroblast Growth Factors; C000589775:Kras protein, zebrafish; D016283:Proto-Oncogene Proteins p21(ras)