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Interplay between VHL/HIF1alpha and Wnt/beta-catenin pathways during colorectal tumorigenesis.

Giles, R.H. and Lolkema, M.P. and Snijckers, C.M. and Belderbos, M. and Groep, P. van der and Mans, D.A. and Beest, M. van and Noort, M. van and Goldschmeding, R. and Diest, P.J. van and Clevers, J.C. and Voest, E.E. (2006) Interplay between VHL/HIF1alpha and Wnt/beta-catenin pathways during colorectal tumorigenesis. Oncogene, 25(21), 3065-3070. ISSN 09509232. doi: 10.1038/sj.onc.1209330.

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Activation of the Wnt signaling pathway initiates the transformation of colorectal epithelial cells, although the transition to metastatic cancer requires angiogenesis. We have investigated the expression of the von Hippel-Lindau (VHL) tumor suppressor in the intestines from humans and mice. Here, we show that VHL expression is regulated by TCF4 and is restricted to the proliferative compartment at the bottom of intestinal crypts. Accordingly, VHL is completely absent from the proliferative intestinal pockets of Tcf4(-/-) perinatal mice. We observed complementary staining of the hypoxia-inducible factor (HIF) 1alpha to VHL in normal intestinal epithelium as well as in all stages of colorectal cancer (CRC). To the best of our knowledge, this is the first report demonstrating the presence of nuclear HIF1alpha in normoxic healthy adult tissue. Although we observed upregulated levels of VHL in very early CRC lesions from sporadic and familial adenomatous polyposis patients - presumably due to activated Wnt signaling - a clear reduction of VHL expression is observed in later stages of CRC progression, coinciding with stabilization of HIF1alpha. As loss of VHL in later stages of CRC progression results in stabilization of HIF, these data provide evidence that selection for VHL downregulation provides a proangiogenic impulse for CRC progression.

Item Type:Article
Additional Information:doi: 10.1038/sj.onc.1209330
Institutes:Hubrecht Instituut
ID Code:3599
Deposited On:13 Feb 2009 17:14
Last Modified:10 Dec 2009 13:14

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