Gene expression profiling in a mouse model of Helicobacter‐induced gastric cancer

Abstract

We have previously reported that a synergistic interaction between hypergastrinemia and Helicobacter felis (H. felis) infection accelerates gastric carcinogenesis in mice, but the precise mechanism for this interaction has not been clarified. Consequently, we undertook an oligonucleotide cDNA microarray study to investigate changes in gene expression in this model system. Nevertheless, the possible mechanisms by which this infectious organism is able to promote gastric cancer have not been elucidated for the most part. Data derived from both animal models as well as human studies have pointed to host immune responses, particularly strong T-helper (Th)1 immune responses, as critical to the development of gastric atrophy and intestinal metaplasia, preneoplastic conditions strongly associated with progression to cancer. (4,5) However, more recent studies in mice have also suggested a role for hypergastrinemia in the pathogenesis of gastric cancer. Hypergastrinemic mice (INS-GAS mice) developed by our group showed spontaneous development of gastric atrophy, metaplasia and adenocarcinoma which could be markedly accelerated by concurrent Helicobacter infection. (6) Kanda et al. also recently reported their gastrin transgenic mice (ACT-GAS mice) showed gastric mucosal hypertrophy and eventually gastric cancer, which was significantly regressed by cyclooxygenase-2 inhibitor celecoxib.(7) In addition, it has been well-documented that hypergastrinemia was associated with tumor growth in human gastric cancer patients.These data suggest the notion that elevations in circulating amidated gastrin might directly promote gastric atrophy and preneoplasia as well as neoplasia of the stomach in a susceptible host. A direct role for amidated gastrin in gastric carcinogenesis has been confirmed in recent studies by our group with the CCK2/gastrin receptor antagonist, YF476, which was shown to inhibit the development of atrophy and cancer in Helicobacterinfected INS-GAS mice.(9) Nevertheless, the relevant downstream targets of gastrin, and the mechanism of synergy between amidated gastrin and Helicobacter infection, has not been defined.The high throughput cDNA microarray represents a powerful tool for analyzing molecular events in cancer progression. This technology has been applied to study of the gene expression patterns in both human tissues and animal models of gastric cancer.(10-12) For example, we have recently reported in Helicobacter felis-infected C57BL/6 mice the gene expression profile of spasmolytic-polypeptide expressing metaplasia (SPEM), a precancerous lesion associated with gastric neoplasia in both rodent and human gastric fundus, and identified 11 SPEM-specific transcripts.(13) However, previous studies did not distinguish and characterize expression profiles based on Helicobacter infection status or serum gastrin levels. Other microarray studies have focused primarily on Helicobacter-treated gastric cancer cell lines, (14) but these in vitro experiments could not correlate the expression of specific genes with can...

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

“…Gastrin has been reported to have a growth factor-like effect on gastric cells, and we have previously reported that Reg I, amphiregulin, and some of MMP family members, such as MMP-7, -9, -10, and -13 were up-regulated in INS-GAS mice of FVB/N background. 23,26,27 In the current study, we confirmed up-regulation of these genes except MMP-7 and -10 as shown in Figure 6, A-C. Previously we have reported that H. felis or H. pylori infection of INS-GAS male mice in an FVB/N background rapidly leads to corpus gastric cancer at 7 to 8 MPI.…”

“…23 Based on these earlier observations, we performed quantitative real-time RT-PCR analysis of these genes in the stomachs of three groups of mice. As expected, gene expression for both Reg I and amphiregulin was significantly up-regulated in infected INS-GAS mice compared with infected GAS-KO and B6 wild-type mice at 12 MPI ( Figure 6A).…”

Expression profile of REG family proteins REG Iα and REG IV in advanced gastric cancer: comparison with mucin phenotype and prognostic markers

“…19 At present, REG family proteins are classified into four subfamilies according to their primary structures, 20 and their overexpression has been reported in neoplastic or inflamed tissues in various organs including the stomach, colorectum, bile duct, and pancreas. [5][6][7][8]14,21,22 Interestingly, microarray analyses suggest that expression of the REG Ia and REG IV genes is prominently upregulated during the development of gastric cancer, 10,11 and in fact we found immunohistochemically that not only REG Ia but also REG IV protein was overexpressed in a considerable number of gastric cancers. However, we also found that REG Ia and REG IV were not always coexpressed in a subset of gastric cancers.…”

“…4 Among human REG family proteins, REG Ia and REG IV are reportedly overexpressed in a subset of gastric cancer. [5][6][7][8][9] Moreover, several microarray analyses have recently isolated REG Ia and REG IV as novel genes that are overexpressed in gastric cancer tissues, 10,11 suggesting that both genes have important functions in gastric carcinogenesis. Indeed, we have previously clarified that REG Ia acts as a trophic and/or anti-apoptotic factor in the development of gastric cancer, 12 and others have reported that REG IV protein confers cell resistance to chemotherapeutic agents, 9 suggesting that these proteins are both associated with tumor progression.…”

Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer

“…Decreased apoA-I levels have been reported in the serum of patients with pancreatic cancer, gastric cancer, and ovarian cancer (4,37,38). Serum apoA-I levels are also down-regulated in patients with lymphoblastic leukemia (39).…”