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Abstract

Cyclooxygenase-2 (COX-2) expression and certain growth hormones, such as gastrin, have been related to gastric carcinogenesis, but little is known about the factors that enhance this COX-2 expression and whether specific blockade of this enzyme has any influence on tumor growth and progression. Our objective was to determine the influence of a specific COX-2 inhibitor, rofecoxib (Vioxx), on serum and tumor levels of gastrin and its precursor, progastrin, as well as on tumor gene expression of COX-2, peroxisome proliferator-activated receptor gamma (PPARgamma), and apoptosis-related proteins (Bax and Bcl-2, caspase-3, and survivin). Twenty-four gastric cancer (GC) patients entered this study and were examined twice, once before and then following a 14-day treatment with Vioxx at a dose of 25 mg twice daily. For comparison, 48 age- and sex-matched healthy controls and 24 similarly matched Helicobacter pylori (Hp)-positive subjects were enrolled and treated with Vioxx as GC patients. Serum levels of anti-Hp and anti-CagA antibodies as well as IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay (ELISA), while serum and tumor contents of progastrin and amidated gastrin were determined by specific RIA. Tumor gene and protein expressions of COX-2, PPARgamma, Bax and Bcl-2, caspase-3, and survivin were determined by RT-PCR and western blot. The overall Hp and CagA seropositivity in 24 GC patients was significantly higher (82% and 47%) than in 48 controls (61% and 22%) but not in 24 Hp-infected subjects (100% and 38%). Serum IL-8 and TNF-alpha values were significantly higher in GC patients than in controls without GC or Hp-infected controls. Median serum progastrin and gastrin levels were found to be significantly higher in GC than in controls without GC and in Hp-positive subjects. Treatment of GC patients with Vioxx resulted in a significant decrease in plasma and tumor contents of both progastrin and gastrin, and this was accompanied by the increment in tumor expression of COX-2, PPARy, Bax, and caspase-3 with a concomitant reduction in Bcl-2 and survivin expression. We conclude that: (1) GC patients show significantly higher Hp and CagA seropositivity than age- and sex-matched controls, but not Hp-positive subjects, indicating that infection with cytotoxic Hp is linked to GC. (2) Serum progastrin and gastrin levels are significantly higher in GC patients than in matched controls, confirming that both gastrins may be implicated in gastric carcinogenesis. (3) GC patients exhibit significantly higher levels of IL-8 and TNF-alpha than non-GC controls and Hp-positive subjects, probably reflecting more widespread gastritis in GC. (4) COX-2, PPARgamma, Bcl-2, and survivin were overexpressed in gastric tumor, but the inhibition of COX-2 activity by Vioxx resulted in a significant reduction in serum and tumor levels of progastrin and gastrin and serum IL-8 and TNF-alpha levels, suggesting that gastrin and proinflammatory cytokines could mediate the up-regulation of COX-2 in gastric cancerogenesis. (5) Vioxx ...

CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis

“…253248 Given that CCK2R is expressed at higher levels in the stomach, 25 where a physiological role is well established, and that progastrin is overexpressed in some gastric cancers, 49 antagonising progastrin signalling could theoretically be effective as therapy in some distal gastric cancers. Nevertheless, we have also shown that amidated gastrin, the most abundant form of gastrin that signals through CCK2R, inhibits antral gastric cancer.…”

Epidermal Growth Factor-activated Aryl Hydrocarbon Receptor Nuclear Translocator/HIF-1β Signal Pathway Up-regulates Cyclooxygenase-2 Gene Expression Associated with Squamous Cell Carcinoma

“…It is well documented that COX-2 expression contributes to increased antiapoptotic, proangiogenic, and metastatic potential in cancer cells, and COX-2 deregulation is correlated with tumor progression (8,9). COX-2-derived PGE 2 stimulates angiogenesis via HIF-1␣, leading to the induction of vascular endothelial growth factor (10). Transcriptional up-regulation of the COX-2 gene by epidermal growth factor receptor (EGFR) and ErbB-2 has been found in cultured cancer cells (11)(12)(13)(14).…”

Non-Steroidal Anti-Inflammatory Drugs in the Carcinogenesis of the Gastrointestinal Tract

“…Treatment of GC patients with rofecoxib (50 mg/day) resulted in a significant decrease in plasma and tumour contents of both progastrin and gastrin levels, and this was accompanied by the increased expression of proapoptptic proteins such as Bax and caspase-3 with a concomitant reduction in Bcl-2 and survivin expression. The blockade of COX-2 was also associated with a decrease in the serum level of proinflammatory cytokines IL-8 and TNFα being also involved in the gastric carcinogenesis [103]. …”