Journal Article

Neurotensin receptor 1 gene activation by the Tcf/β-catenin pathway is an early event in human colonic adenomas

Frédérique Souazé, Véronique Viardot-Foucault, Nicolas Roullet, Mireille Toy-Miou-Leong, Anne Gompel, Erik Bruyneel, Eva Comperat, Maree C Faux, Marc Mareel, William Rostène, Jean-François Fléjou, Christian Gespach and Patricia Forgez

in Carcinogenesis

Volume 27, issue 4, pages 708-716
Published in print April 2006 | ISSN: 0143-3334
Published online November 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi269
Neurotensin receptor 1 gene activation by the Tcf/β-catenin pathway is an early event in human colonic adenomas

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Alterations in the Wnt/APC (adenomatous polyposis coli) signalling pathway, resulting in β-catenin/T cell factor (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 G-protein coupled receptor, 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 upregulation of NT1 receptor occurring in colon cancer is the result of Wnt/APC signalling 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 β-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 breakdown in NT-induced intracellular calcium mobilization 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 β-catenin localization while NT1 receptor was absent when β-catenin was localized at the cell–cell junction in early adenomas of patients with familial adenomatous polyposis, hereditary non-polyposis colorectal cancer and loss of heterozygosity tumours. In this report we establish a novel link in vitro between the Tcf/β-catenin pathway and NT1 receptor promoter activation.

Keywords: ANM, adjacent normal mucosa; APC, adenomatous polyposis coli; FAP, familial adenomatous polyposis; FCS, fetal calf serum; GPCR, G-protein coupled receptors; GSK, glycogen synthase kinase; HGF, hepatocyte growth factor; HNPCC, hereditary non-polyposis colorectal cancer; HBEC, human breast epithelial cells; JMV 449, H-LysΨ(CH2NH)Lys-Pro-Tyr-Ile-Leu-OH; NT, neurotensin; LEF, lymphoid enhancer factor; Tcf, T cell factor

Journal Article.  6927 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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