Nguyen, A.T., Emelyanov, A., Koh, C.H., Spitsbergen, J.M., Lam, S.H., Mathavan, S., Parinov, S., and Gong, Z. (2011) A high level of liver-specific expression of oncogenic KrasV12 drives robust liver tumorigenesis in transgenic zebrafish. Disease models & mechanisms. 4(6):801-13.
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 krasV12 specifically in the transgenic zebrafish liver. Only a high level of krasV12 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 krasV12 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 krasV12-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.
