Please use this identifier to cite or link to this item: https://doi.org/10.1242/dmm.008367
DC FieldValue
dc.titleAn inducible kras V12 transgenic zebrafish model for liver tumorigenesis and chemical drug screening
dc.contributor.authorNguyen, A.T.
dc.contributor.authorEmelyanov, A.
dc.contributor.authorKoh, C.H.V.
dc.contributor.authorSpitsbergen, J.M.
dc.contributor.authorParinov, S.
dc.contributor.authorGong, Z.
dc.date.accessioned2014-10-27T08:21:39Z
dc.date.available2014-10-27T08:21:39Z
dc.date.issued2012-01
dc.identifier.citationNguyen, 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
dc.identifier.issn17548403
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/100069
dc.description.abstractBecause 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.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1242/dmm.008367
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentBIOLOGICAL SCIENCES
dc.description.doi10.1242/dmm.008367
dc.description.sourcetitleDMM Disease Models and Mechanisms
dc.description.volume5
dc.description.issue1
dc.description.page63-72
dc.identifier.isiut000300642200009
Appears in Collections:Staff Publications

Show simple item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

122
checked on May 10, 2022

WEB OF SCIENCETM
Citations

117
checked on May 10, 2022

Page view(s)

209
checked on May 12, 2022

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.