Neurotensin receptor 1 gene activation by the Tcf/β-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.

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

“…To consolidate activation of the b-catenin signal by CagA, WT-A10 cells were cultured in the presence or absence of Dox and, at 36 h after onset of CagA induction, total RNAs were isolated and were subjected to a genome-wide cDNA microarray analysis. Among genes upregulated by CagA were p21, cyclin D1 and several other b-catenindependent genes such as ECM1 and Neurotensin receptor 1 (Kenny et al, 2005;Souaze´et al, 2006). Sequential induction of p21 and cyclin D1 by CagA indicated that the bacterial protein generates both growth-inhibitory and growth-stimulatory signals in a single cell.…”

Neurotensin Receptor 1 Determines the Outcome of Non–Small Cell Lung Cancer

“…As previously described, one of the possible molecular mechanisms responsible for NTSR1 upregulation is the Wnt/APC signaling pathway activation, because of a functional Tcf element within the NTSR1 promoter. In normal human breast epithelial cells, the activation of the NTSR1 gene was observed by agents causing β-catenin cytosolic accumulation (15). A set of TCF4 regulated genes was recently shown to be associated with metastasis-free survival in patients with lung adenocarcinoma (27).…”

“…(11)(12)(13). The disruption of the neurotensinergic pathway through a specific antagonist, in experimental tumors from colon, breast, and small cell lung cancer cells, caused a strong reduction in tumor growth (14)(15)(16). We had previously shown the presence of a chronic self-activation loop between neurotensin and NTSR1, as one mechanism responsible for the constitutive activation of the mitogen-activated protein kinase mitogenic signaling pathways along with sustained target gene activation (17)(18)(19)(20).…”

NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

“…[49][50][51][52] Therefore, these types of neoplasia are potential targets for NT-polyplex transfection and open the possibility of exploring new approaches of gene therapy for cancer. …”