Signaling Pathways Associated with Colonic Mucosa Hyperproliferation in Mice Overexpressing Gastrin Precursors

Abstract

MTI/G-Gly mice and hGAS mice, overexpressing glycineextended gastrin (G-Gly) and progastrin, respectively, display colonic mucosa hyperplasia, hyperproliferation, and an increased susceptibility to intestinal neoplasia. Here, we have used these transgenic mice to analyze in vivo the modulation of intracellular signaling pathways that may be responsible for the proliferative effects of gastrin precursors. The expression, activation, and localization of signaling and cell-to-cell adhesion molecules were studied using immunofluorescence and Western blot techniques on colonic tissues derived from MTI/G-Gly, hGAS, or wild-type FVB/N mice. These analyses revealed an up-regulation of Src tyrosine kinase and related signaling pathways [phosphatidyl inositol 3V -kinase (PI3K)/ Akt, Janus-activated kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, and extracellular-signal regulated kinases (ERK)] in both MTI/G-Gly and hGAS mice compared with the wild-type control animals as well as an overexpression of transforming growth factor-A (TGF-A). In contrast, overexpression of the gastrin precursors did not affect the activation status of STAT1 nor the expression and the distribution of adhesion proteins ( focal adhesion kinase, cadherins, and catenins). We report for the first time that the transition from a normal colonic epithelium to a hyperproliferative epithelium in MTI/G-Gly and hGAS mice may be a consequence of the up-regulation of Src, PI3K/Akt, JAK2, STAT3, ERKs, and TGF-A. Deregulation of cell adhesion, a late event in tumor progression, does not occur in these transgenic models. (Cancer Res 2005; 65(7): 2770-7)

A New Biomarker That Predicts Colonic Neoplasia Outcome in Patients with Hyperplastic Colonic Polyps

“…The role of progastrin in proliferation, survival, and migration of human colon cancer cells has also been clearly established (15)(16)(17)(18)(19)(20). Progastrin growth-promoting effects are mediated through the activation of several key signal transduction pathways (21,22). In addition, several works including ours showed that depletion of endogenous progastrin produced by colon cancer cells leads to an inhibition of tumor growth (23,24).…”

Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells

“…AIIt was identified as a receptor for plasmin-induced signaling in human peripheral monocytes, which involved the activation of nuclear factor (NF)-kB, JAK/ signal transducers and activators of transcription (STAT) and p38 mitogen-activated protein kinase (MAPK) signaling cascades, leading to a full-scale proinflammatory response (Laumonnier et al, 2006). It is possible, that binding of PG to ANX II may mediate an activation of a similar cascade of signaling molecules in target cells, as we and others have reported activation of Src, phosphatidylinositol 3 0 -kinase/Akt, JAK2, STAT5/3, extracellular signal-regulated kinases, p38 MAPK and NFkB, in response to PG Brown et al, 2003;Ferrand et al, 2005;Rengifo-Cam and Singh, 2005). Importantly, our preliminary findings suggest that treatment of IEC-18 cells with anti-ANX II-Abs results in attenuating the activation of many of the above-described signaling molecules, in response to PG (unpublished data from our laboratory).…”

“…Our current studies suggest that PG/gastrins bind membrane-associated ANX II, which perhaps leads to colocalization and activation of ANX II and c-Src kinase. The latter possibility is highlighted by the fact that PG/gastrins activate c-Src kinase in target cells (Singh et al, 1994c;Brown et al, 2003;Ferrand et al, 2005).…”

“…Interestingly, treatment of human astrocytoma U373 cells with gastrin resulted in overexpression of TN-C and S100A6 (Kucharczak et al, 2001). As c-Jun and NF-kB synergistically transactivate TN-C promoter in primary rat embryo fibroblasts (Mettouchi et al, 1997), gastrin may activate TN-C promoter in glioblastoma cells via the same signaling molecules known to be activated in response to PG/ gastrins in other cells (Ferrand et al, 2005;RengifoCam and Singh, 2005).…”

Zinc ions upregulate the hormone gastrin via an E-box motif in the proximal gastrin promoter

“…Several candidates, including annexin II (Singh et al 2007) and the F1 subunit of the mitochondrial ATPase (Kowalski-Chauvel et al 2012), have been identified as possible receptors for progastrin and glycine-extended gastrin respectively. Progastrin and progastrin-derived peptides including Ggly and gastrin are biologically active and have growth-promoting effects on normal and cancerderived gastrointestinal cells in vitro and in vivo , Aly et al 2001, Pannequin et al 2002, Ferrand et al 2005, Takaishi et al 2009). …”