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|Title:||An inducible kras V12 transgenic zebrafish model for liver tumorigenesis and chemical drug screening||Authors:||Nguyen, A.T.
|Issue Date:||Jan-2012||Citation:||Nguyen, A.T., Emelyanov, A., Koh, C.H.V., Spitsbergen, J.M., Parinov, S., Gong, Z. (2012-01). An inducible kras V12 transgenic zebrafish model for liver tumorigenesis and chemical drug screening. DMM Disease Models and Mechanisms 5 (1) : 63-72. ScholarBank@NUS Repository. https://doi.org/10.1242/dmm.008367||Abstract:||Because Ras signaling is frequently activated by major hepatocellular carcinoma etiological factors, a transgenic zebrafish constitutively expressing the kras V12 oncogene in the liver was previously generated by our laboratory. Although this model depicted and uncovered the conservation between zebrafish and human liver tumorigenesis, the low tumor incidence and early mortality limit its use for further studies of tumor progression and inhibition. Here, we employed a mifepristone-inducible transgenic system to achieve inducible kras V12 expression in the liver. The system consisted of two transgenic lines: the liver-driver line had a liver-specific fabp10 promoter to produce the LexPR chimeric transactivator, and the Ras-effector line contained a LexA-binding site to control EGFP-kras V12 expression. In double-transgenic zebrafish (driver-effector) embryos and adults, we demonstrated mifepristone-inducible EGFP-kras V12 expression in the liver. Robust and homogeneous liver tumors developed in 100% of double-transgenic fish after 1 month of induction and the tumors progressed from hyperplasia by 1 week post-treatment (wpt) to carcinoma by 4 wpt. Strikingly, liver tumorigenesis was found to be 'addicted' to Ras signaling for tumor maintenance, because mifepristone withdrawal led to tumor regression via cell death in transgenic fish. We further demonstrated the potential use of the transparent EGFP-krasV12 larvae in inhibitor treatments to suppress Ras-driven liver tumorigenesis by targeting its downstream effectors, including the Raf-MEK-ERK and PI3K-AKT-mTOR pathways. Collectively, this mifepristone- inducible and reversible kras V12 transgenic system offers a novel model for understanding hepatocarcinogenesis and a high-throughput screening platform for anti-cancer drugs. © 2012. Published by The Company of Biologists Ltd.||Source Title:||DMM Disease Models and Mechanisms||URI:||http://scholarbank.nus.edu.sg/handle/10635/100069||ISSN:||17548403||DOI:||10.1242/dmm.008367|
|Appears in Collections:||Staff Publications|
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