APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression

Janssen, Klaus-Peter, Alberici, Paola, Fsihi, Hafida, Gaspar, Claudia, Breukel, Cor, Franken, Patrick, Rosty, Christophe, Abal, Miguel, El Marjou, Fatima, Smits, Ron, Louvard, Daniel, Fodde, Riccardo and Robine, Sylvie (2006) APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology, 131 4: 1096-1109. doi:10.1053/j.gastro.2006.08.011

Author Janssen, Klaus-Peter
Alberici, Paola
Fsihi, Hafida
Gaspar, Claudia
Breukel, Cor
Franken, Patrick
Rosty, Christophe
Abal, Miguel
El Marjou, Fatima
Smits, Ron
Louvard, Daniel
Fodde, Riccardo
Robine, Sylvie
Title APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression
Journal name Gastroenterology   Check publisher's open access policy
ISSN 0016-5085
Publication date 2006-10
Sub-type Article (original research)
DOI 10.1053/j.gastro.2006.08.011
Volume 131
Issue 4
Start page 1096
End page 1109
Total pages 14
Place of publication Bethesda, MD, United States
Publisher W.B. Saunders
Language eng
Abstract Background & Aims: Synchronous activation of the Wnt signaling pathway, mostly because of loss of function of the APC tumor suppressor, and of the oncogenic KRAS-signaling pathway is very frequent in colorectal cancer and is associated with poor prognosis. Methods: We have generated a compound transgenic mouse model, KRASV12G/Apc+/1638N, to recapitulate the human disease and compared it with single transgenic littermates. Results: Compound mutant mice are characterized by a 10-fold increase in tumor multiplicity and by accelerated tumor progression, resulting in strongly enhanced morbidity and mortality. Tumors from compound mutant mice proliferate faster and show decreased levels of apoptosis. Several lines of evidence indicate that the observed increase in tumor multiplicity and malignant transformation is caused by the synergistic activation of Wnt signaling in cells with oncogenic KRAS and loss-of-function Apc mutations. Activated KRAS is known to induce tyrosine phosphorylation of β-catenin, leading to its release from E-cadherin at the adherens junction. This results in an increased β-catenin pool in the cytoplasma, its subsequent translocation to the nucleus, and the transcriptional activation of Wnt downstream target genes. Accordingly, intestinal tumors from KRASV12G/Apc+/1638N mice show a significant increase in cells with nuclear accumulation of β-catenin when compared with Apc+/1638N animals. Moreover, Apc/KRAS-mutant embryonic stem cells show a significantly enhanced β-catenin/T-cell factor-mediated transcriptional activation, accompanied by increased β-catenin nuclear localization. Conclusions: This KRAS-induced increase in Wnt/β-catenin signaling may enhance the plasticity and self-renewal capacity of the tumor, thus resulting in the drastically augmented tumor multiplicity and malignant behavior in compound mutant animals.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Centre for Clinical Research Publications
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Created: Wed, 09 Mar 2011, 14:21:00 EST