Gastrin Is an Essential Cofactor for Helicobacter-Associated Gastric Corpus Carcinogenesis in C57BL/6 Mice

Abstract

We have previously described a synergistic interaction between hypergastrinemia and Helicobacter felis infection on gastric corpus carcinogenesis in FVB/N mice housed under specific-pathogen-free conditions. However, gastrin-deficient (GAS-KO) mice on a mixed C57BL/6/129Sv genetic background maintained in conventional housing were reported to develop spontaneous gastric antral tumors. Therefore, we investigated the role of gastrin in Helicobacterassociated gastric carcinogenesis in H. felis-infected mice on a uniform C57BL/6 background housed in specific-pathogen-free conditions. Hypergastrinemic transgenic (INS-GAS) mice, GAS-KO mice, and C57BL/6 wild-type mice were infected with H. felis for either 12 or 18 months. At 12 months postinfection, INS-GAS mice had mild corpus dysplasia, while B6 wild-type mice had either severe gastritis or metaplasia, and GAS-KO mice had only mild to moderate gastritis. At 18 months postinfection, both INS-GAS and B6 wild-type mice had both severe atrophic gastritis and corpus dysplasia, while GAS-KO mice had severe gastritis with mild gastric atrophy, but no corpus dysplasia. In contrast, both GAS-KO and B6 wildtype mice had mild to moderate antral dysplasia, while INS-GAS mice did not. H. felis antral colonization remained stable over time among the three groups of mice. These results point to a distinct effect of gastrin on carcinogenesis of both the gastric corpus and antrum, suggesting that gastrin is an essential cofactor for gastric corpus carcinogenesis in C57BL/6 mice. Gastric cancer remains the second leading cause of cancer-related mortality in the world, although its incidence and mortality rates have been decreasing in the United States over the past 70 years.

Human gastrin mRNA expression up-regulated by Helicobacter pylori CagA through MEK/ERK and JAK2-signaling pathways in gastric cancer cells

“…Asymptomatic patients with H. pylori colonization have elevated serum gastrin concentrations [15], and following the eradication of H. pylori, there is a reduction of serum gastrin concentration in fasting patients [16]. In 2009, Takaishi et al [17] found a marked effect of gastrin on carcinogenesis of both the gastric corpus and the antrum in mice with H. pylori infection, suggesting that gastrin and H. pylori are essential cofactors for carcinogenesis of the gastric corpus. However, the correlation between H. pylori infection and gastrin expression in gastric carcinogenesis has been unclear.…”

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). …”

In vivo analysis of mouse gastrin gene regulation in enhanced GFP-BAC transgenic mice

“…H. felis colonization levels in gastric tissue were quantified by real-time PCR assay with H. felis flagellar filament B (flaB) primers using QuantiTect SYBR Green PCR kit (QIAGEN) and 7300 real-time PCR system (Applied Biosystems) as previously described (36,37). The number of genomic copies of H. felis colonies was normalized by comparison to GAPDH level determined by quantitative PCR (qPCR), which was assumed to represent endogenous stomach genomic DNA quantity.…”

“…PCR amplification was performed by 7300 real-time PCR system (Applied Biosystems) under the following conditions: 94°C for 15 min, followed by 40 cycles at 94°C for 10 s, 55°C for 20 s, and 72°C for 30 s, then 1 cycle of 72°C for 10 min. The expression level of each gene was normalized to the expression level of internal control GAPDH by the ⌬⌬Ct method as previously described (36,37).…”