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BCL9-2 promotes early stages of intestinal tumor progression

Official URL:https://doi.org/10.1053/j.gastro.2011.06.039
PubMed:View item in PubMed
Creators Name:Brembeck, F.H. and Wiese, M. and Zatula, N. and Grigoryan, T. and Dai, Y. and Fritzmann, J. and Birchmeier, W.
Journal Title:Gastroenterology
Journal Abbreviation:Gastroenterology
Volume:141
Number:4
Page Range:1359-1370
Date:October 2011
Keywords:Colon Cancer, Carcinogenesis, Mouse Model, Animals, Mice
Abstract:BACKGROUND & AIMS: The roles of the 2 BCL9 and 2 Pygopus genes in Wnt to beta-catenin signaling are not clear in vertebrates. We examined their expression and function in normal and tumor intestinal epithelia in mice and humans. METHODS: Specific antibodies were generated to characterize the BCL9 and Pygopus proteins in normal intestine and in colon tumors. Targets of BCL9 and Pygopus in colon cancer cells were analyzed using small interfering (si) RNA analysis. Trangenic mice were created that overexpressed BCL9-2 in intestine; these were crossed with APC(Min/+) mice to create BCL9-2;APC(Min/+) mice. RESULTS: BCL9 and Pygopus2 were expressed in all normal intestinal and colon cancer cells. BCL9-2 was detectable only in the villi-not in the crypts of normal intestine. BCL9-2 was upregulated in adenomas and in almost all colon tumors, with a concomitant increase of Pygopus2, whereas levels of BCL9 were similar between normal and cancer cells. Transgenic overexpression of BCL9-2 in the intestine of BCL9-2; APC(Min/+) mice increased formation of adenomas that progressed to invasive tumors, resulting in reduced survival time. Using siRNA analysis, we found that BCL9s and Pygopus are not targets of Wnt in colon cancer cells, but Wnt signaling correlated with levels of BCL9-2. BCL9-2 regulated expression of beta-catenin-dependent and -independent target genes that have been associated with early stages of intestinal tumorigenesis. DISCUSSION: BCL9-2 promotes early phases of intestinal tumor progression in humans and in transgenic mice. BCL9-2 increases the expression of a subset of canonical Wnt target genes, but also regulates genes that are required for early stages of tumor progression.
ISSN:0016-5085
Publisher:Saunders (U.S.A.)
Item Type:Article

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