A gastrin precursor, gastrin‐gly, upregulates VEGF expression in colonic epithelial cells through an HIF‐1‐independent mechanism

Abstract

One of the major angiogenic factor released by tumor cells is VEGF. Its high expression is correlated with poor prognosis in colorectal tumors. In colon cancer, gastrin gene expression is also upregulated. In these tumors, gastrin precursors are mainly produced and act as growth factors. Recently, a study has also shown that the gastrin precursor, G-gly induced in vitro tubules formation by vascular endothelial cells suggesting a potential proangiogenic role. Here, we demonstrate that stimulation of human colorectal cancer cell lines with G-gly increases the expression of the proangiogenic factor VEGF at the mRNA and protein levels. In addition, blocking the progastrin autocrine loop leads to a downregulation of VEGF. Although HIF-1 is a major transcriptional activator for VEGF our results suggest an alternative mechanism for VEGF regulation in normoxic conditions, independent of HIF-1 that involves the PI3K/AKT pathway. Indeed we show that G-gly does not lead to HIF-1 accumulation in colon cancer cells. Moreover, we found that G-gly activates the PI3K/AKT pathway and inhibition of this pathway reverses the effects of G-gly observed on VEGF mRNA and protein levels. In correlation with these results, we observed in vivo, on colon tissue sections from transgenic mice overexpressing G-gly, an increase in VEGF expression in absence of HIF-1 accumulation. In conclusion, our study demonstrates that gastrin precursors, known to promote colon epithelial cells proliferation and survival can also contribute to the angiogenesis process by stimulating the expression of the proangiogenic factor VEGF via the PI3K pathway and independently of hypoxia conditions.

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

“…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). Moreover, high concentrations of progastrin are found in colon tumors and in blood of 80% of patients with colorectal cancer.…”

Identification of the F1-ATPase at the Cell Surface of Colonic Epithelial Cells

“…Analysis by confocal microscopy shows a ␤F 1 staining on the cell surface of two colon cancer cell lines, HCT116 and HT29, in which we previously reported a biological effect of G-gly (Fig. 6, a and d) (9,28). These results suggest that the orientation of the F1-ATPase in the membrane is such that the F1 component is extracellular and available to the antibody.…”

Progastrin: a potential predictive marker of liver metastasis in colorectal cancer

“…Evidence from in vitro and in vivo studies suggests that PG and Ggly act as mitogens [1], promote resistance against a range of apoptotic stimuli [2,3], stimulate angiogenesis [4,5], induce perturbations in intercellular adhesion and promote cell migration and invasion, including increased expression of several matrix metalloproteinases [6]. These data suggest that PG and Ggly may have an important role in CRC tumourigenesis and that their expression may predict clinical outcome.…”