2000 - 2001: The GAST gene is a target of the ß-catenin /Tcf4 pathway. The presence of hPG80 is demonstrated in the plasma of colorectal cancer patients. 2005: Ras and ß-catenin /Tcf4 pathways induce synergistic activation of the GAST gene, contributing to possible neoplastic progression. 2007: Inhibition of hPG80 expression inhibits the Wnt/ ß-catenin pathway inducing decreased growth and tumor differentiation in intestinal tumor models. Wnt and K-Ras The first event leading to colon cancer is in 80 to 90\% of cases a constitutive activation of the Wnt/ ß-catenin oncogenic pathway induced by mutations in the APC (Adenomatous polyposis coli) coding gene or the ß-catenin coding gene. Mutations induction into normal intestinal stem cells is sufficient to trigger tumorigenesis. GAST gene which encodes hPG80 is activated by the Wnt oncogenic pathway. It is a downstream target of the ß-catenin /Tcf-4 signaling pathway. Since both K-Ras and the Wnt pathway induce GAST expression, the hypothesis of a possible cooperation between these two pathways to regulate hPG80 expression was investigated. Chakadar and al. found significant synergistic stimulation of the GAST gene promoter (by a factor of 25-40) by a combination of oncogenic ß-catenin and K-Ras overexpression. Activation of the GAST gene promoter was also shown to be dependent on other signalling signals: enhanced or suppressed by co-expression of wild-type SMAD4 or by a dominant negative mutant of SMAD4, respectively, and abrogated by inhibition of PI3K. Thus, constitutive activation of the Wnt pathway, considered to be at the onset of tumorigenesis in the colon, and the K-Ras oncogene, present in 50\% of human colorectal tumors, synergistically stimulate the production of hPG80, a tumorigenesis promoter. Tumorigenesis induced by activation of the Wnt pathway is partially dependent on hPG80. One candidate is Annexin A2, identified as being able of binding progastrin and derived peptides. Annexin A2 is a partial mediator of the effect of progastrin/gastrins. In particular, Annexin A2 mediates NF-kappaB upregulation and ß-catenin in response to progastrin in mice and HEK-293 cells. In addition, annexin A2 may be involved in progastrin-dependent clathrin endocytosis. However, progastrin affinity for Annexin A2 is not what would be expected for a specific receptor. And, although Annexin A2 plays a role in progastrin functions, it does not fit a receptor function.
2000 - 2001: The GAST gene is a target of the β-catenin /Tcf4 pathway. The presence of hPG80 is demonstrated in the plasma of colorectal cancer patients. 2005: Ras and β-catenin /Tcf4 pathways induce synergistic activation of the GAST gene, contributing to possible neoplastic progression. 2007: Inhibition of hPG80 expression inhibits the Wnt/ β-catenin pathway inducing decreased growth and tumor differentiation in intestinal tumor models. Wnt and K-Ras The first event leading to colon cancer is in 80 to 90\% of cases a constitutive activation of the Wnt/ β-catenin oncogenic pathway induced by mutations in the APC (Adenomatous polyposis coli) coding gene or the β-catenin coding gene. Mutations induction into normal intestinal stem cells is sufficient to trigger tumorigenesis. GAST gene which encodes hPG80 is activated by the Wnt oncogenic pathway. It is a downstream target of the β-catenin /Tcf-4 signaling pathway. Since both K-Ras and the Wnt pathway induce GAST expression, the hypothesis of a possible cooperation between these two pathways to regulate hPG80 expression was investigated. Chakadar and al. found significant synergistic stimulation of the GAST gene promoter (by a factor of 25-40) by a combination of oncogenic β-catenin and K-Ras overexpression. Activation of the GAST gene promoter was also shown to be dependent on other signalling signals: enhanced or suppressed by co-expression of wild-type SMAD4 or by a dominant negative mutant of SMAD4, respectively, and abrogated by inhibition of PI3K. Thus, constitutive activation of the Wnt pathway, considered to be at the onset of tumorigenesis in the colon, and the K-Ras oncogene, present in 50\% of human colorectal tumors, synergistically stimulate the production of hPG80, a tumorigenesis promoter. Tumorigenesis induced by activation of the Wnt pathway is partially dependent on hPG80. One candidate is Annexin A2, identified as being able of binding progastrin and derived peptides. Annexin A2 is a partial mediator of the effect of progastrin/gastrins. In particular, Annexin A2 mediates NF-kappaB upregulation and β-catenin in response to progastrin in mice and HEK-293 cells. In addition, annexin A2 may be involved in progastrin-dependent clathrin endocytosis. However, progastrin affinity for Annexin A2 is not what would be expected for a specific receptor. And, although Annexin A2 plays a role in progastrin functions, it does not fit a receptor function.
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