title: Neurotensin receptor 1 gene activation by the Tcf/beta-catenin pathway is an early event in human colonic adenomas.
abstract: Alterations in the Wnt/APC (adenomatous polyposis coli) signalling pathway, resulting in beta-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 beta-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 beta-catenin localization while NT1 receptor was absent when beta-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/beta-catenin pathway and NT1 receptor promoter activation.
authors.affiliation: INSERM U673-UPMC, Department of Pathology, 184 Rue Du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Souazé
authors.forename: Véronique
authors.initials: V
authors.lastname: Viardot-Foucault
authors.forename: Nicolas
authors.initials: N
authors.lastname: Roullet
authors.forename: Mireille
authors.initials: M
authors.lastname: Toy-Miou-Leong
authors.forename: Anne
authors.initials: A
authors.lastname: Gompel
authors.forename: Erik
authors.initials: E
authors.lastname: Bruyneel
authors.forename: Eva
authors.initials: E
authors.lastname: Comperat
authors.forename: Maree C
authors.initials: MC
authors.lastname: Faux
authors.forename: Marc
authors.initials: M
authors.lastname: Mareel
authors.forename: William
authors.initials: W
authors.lastname: Rostène
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fléjou
authors.forename: Christian
authors.initials: C
authors.lastname: Gespach
authors.forename: Patricia
authors.initials: P
authors.lastname: Forgez
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000503:physiopathology; D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D019656:Loss of Heterozygosity; D011401:Promoter Regions, Genetic; D018028:Receptors, Neurotensin / Q000096:biosynthesis* / Q000502:physiology; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000502:physiology*; D015854:Up-Regulation; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D018028:Receptors, Neurotensin; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C114036:neurotensin type 1 receptor