Carcinogenesis Advance Access published online on November 19, 2005
Carcinogenesis, doi:10.1093/carcin/bgi269
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1 INSERM U 673 - UPMC, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
* To whom correspondence should be addressed. Alterations in the Wnt/APC signaling pathway, resulting in
Received April 29, 2005
Revised November 3, 2005
Accepted November 9, 2005
CANCER BIOLOGY
Neurotensin receptor 1 gene activation by the Tcf/
Frédérique Souazé 1,
Véronique Viardot-Foucault 1,
Nicolas Roullet 1,
Mireille Toy-Miou-Leong 1,
Anne Gompel 1,
Erik Bruyneel 2,
Eva Comperat 3,
Maree C. Faux 4,
Marc Mareel 2,
William Rostène 5,
Jean-François Fléjou 3,
Christian Gespach 1,
and
Patricia Forgez 1 *
-catenin pathway is an early event in human colonic adenomas
2 The laboratory of Experimental Cancerology, Ghent University Hospital, B-9000 Ghent, Belgium
3 Department of pathology, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
4 Ludwig Institute for Cancer Research, Parkville, Victoria 3050, Australia
5 INSERM. 732 - UPMC, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
Patricia Forgez, E-mail: forgez{at}st-antoine.inserm.fr
Abstract 
-catenin/Tcf dependent transcriptional gene activation, are frequently detected in familial and sporadic colon cancers. The neuropeptide neurotensin (NT) is widely distributed in the gastrointestinal tract. Its proliferative and survival effects are mediated by a GPCR, the NT1 receptor. NT1 receptor is not expressed in normal colon epithelial cells, but is over expressed in a number of cancer cells and tissues suggesting a link to the outgrowth of human colon cancer. Our results demonstrate that the up-regulation of NT1 receptor occurring in colon cancer is the result of Wnt/APC signaling pathway activation. We first established the functionality of the Tcf response element within the NT1 receptor promoter. Consequently, we observed the activation of NT1 receptor gene by agents causing -catenin cytosolic accumulation, as well as a strong decline of endogenous receptor when wt-APC was restored. At the cellular level, the re-establishment of wt-APC phenotype resulted in the impaired functionality of NT1 receptor, like the break down in NT induced intracellular calcium mobilisation and the loss of NT pro-invasive effect. We corroborated the Wnt/APC signalling pathway on the NT1 receptor promoter activation with human colon carcinogenesis, and showed that NT1 receptor gene activation was perfectly correlated with nuclear or cytoplasmic -catenin localisation while NT1 receptor was absent when -catenin was localized at the cell-cell junction in early adenomas of patients with FAP, HNPCC, and LOH tumours. In this report we establish a novel link in vitro between the Tcf/-catenin pathway and NT1 receptor promoter activation.
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