title: A high level of liver-specific expression of oncogenic Kras(V12) drives robust liver tumorigenesis in transgenic zebrafish.
abstract: Human liver cancer is one of the deadliest cancers worldwide, with hepatocellular carcinoma (HCC) being the most common type. Aberrant Ras signaling has been implicated in the development and progression of human HCC, but a complete understanding of the molecular mechanisms of this protein in hepatocarcinogenesis remains elusive. In this study, a stable in vivo liver cancer model using transgenic zebrafish was generated to elucidate Ras-driven tumorigenesis in HCC. Using the liver-specific fabp10 (fatty acid binding protein 10) promoter, we overexpressed oncogenic kras(V12) specifically in the transgenic zebrafish liver. Only a high level of kras(V12) expression initiated liver tumorigenesis, which progressed from hyperplasia to benign and malignant tumors with activation of the Ras-Raf-MEK-ERK and Wnt-β-catenin pathways. Histological diagnosis of zebrafish tumors identified HCC as the main lesion. The tumors were invasive and transplantable, indicating malignancy of these HCC cells. Oncogenic kras(V12) was also found to trigger p53-dependent senescence as a tumor suppressive barrier in the pre-neoplastic stage. Microarray analysis of zebrafish liver hyperplasia and HCC uncovered the deregulation of several stage-specific and common biological processes and signaling pathways responsible for kras(V12)-driven liver tumorigenesis that recapitulated the molecular hallmarks of human liver cancer. Cross-species comparisons of cancer transcriptomes further defined a HCC-specific gene signature as well as a liver cancer progression gene signature that are evolutionarily conserved between human and zebrafish. Collectively, our study presents a comprehensive portrait of molecular mechanisms during progressive Ras-induced HCC. These observations indicate the validity of our transgenic zebrafish to model human liver cancer, and this model might act as a useful platform for drug screening and identifying new therapeutic targets.
authors: Department of Biological Sciences, National University of Singapore, Singapore, 117543.
authors: Anh Tuan
authors: AT
authors: Nguyen
authors: Alexander
authors: A
authors: Emelyanov
authors: Chor Hui Vivien
authors: CH
authors: Koh
authors: Jan M
authors: JM
authors: Spitsbergen
authors: Siew Hong
authors: SH
authors: Lam
authors: Sinnakaruppan
authors: S
authors: Mathavan
authors: Serguei
authors: S
authors: Parinov
authors: Zhiyuan
authors: Z
authors: Gong
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D009857:Oncogenes; D009928:Organ Specificity; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins