Effect of Helicobacter pylori‐Induced Cyclooxygenase‐2 on Gastric Epithelial Cell Kinetics: Implication for Gastric Carcinogenesis

Wambura, Casmir; Aoyama, Nobuo; Shirasaka, Daisuke; Sakai, Toshiyuki; Ikemura, Takahiro; Sakashita, Masanori; Maekawa, Satoshi; Kuroda, Kohei; Inoue, Takashi; Ebara, Sohei; Miyamoto, Masaki; Kasuga, Masato

doi:10.1046/j.1083-4389.2002.00069.x

Cited by 35 publications

(24 citation statements)

References 45 publications

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“…Up-regulation of COX-2 plays a central role in the inflammatory changes and tissue damages associated with the chronic H. pylori infection, and is also involved in the gastric tumorigenesis (4,5). The expression of COX-2 protein is significantly higher in patients with gastric cancer than those with nonulcer dyspepsia (6). Therefore, COX-2 expression is assumed to play a key role in H. pylori-associated gastric cancer in addition to the propagation of gastric inflammation (7).…”

Section: Helicobacter Pylori-induced Invasion and Angiogenesis Of Gasmentioning

confidence: 99%

Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation

Chang¹,

Lin

et al. 2005

The Journal of Immunology

138

113

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Cyclooxygenase-2 (COX-2) plays a crucial role in Helicobacter pylori-associated gastric cancer. In this study, we report that H. pylori-induced COX-2 expression enhances the cancer cell invasion and angiogenesis via TLR2 and TLR9, which can be attenuated by the specific COX-2 inhibitor NS398 or celecoxib. The cAMP response element (CRE) and AP1 sites, but not κB on the COX-2 promoter, are involved in MAPKs-regulated COX-2 expression. Differential bindings of the CREB-1, ATF-2, c-jun to the CRE site, and the c-fos, c-jun, ATF-2 to the AP1 site are demonstrated by DNA affinity protein-binding, supershift, and chromatin immunoprecipitation assays. Activations of these transcription factors were attenuated by different MAPKs inhibitors. The mutants of TLR2, TLR9, or MAPKs inhibited H. pylori-induced COX-2 promoter, CRE, and AP-1 activities. MAPKs inhibitors attenuated the H. pylori-induced COX-2 mRNA and protein expressions. These results indicate that H. pylori acts through TLR2 and TLR9 to activate MAPKs, especially p38, and their downstream transcription factors (CREB-1, ATF-2, c-jun, and c-fos), resulting in the activations of CRE and AP-1 on the COX-2 promoter. These intracellular networks drive the COX-2-dependent PGE2 release and contribute to cell invasion and angiogenesis.

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Section: Helicobacter Pylori-induced Invasion and Angiogenesis Of Gasmentioning

confidence: 99%

Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation

Chang¹,

Lin

et al. 2005

The Journal of Immunology

138

113

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“…H pylori infection could also induce gastric mucosal cell proliferation by COX-2 expression. COX-2 gene expression was one of the related factors mediating the progress from gastritis with H pylori infection to pre-carcinoma lesions even gastric carcinoma [16,17] . Based on this study, treatment of H pylori infection and special COX-2 inhibitor could be useful for the prevention of gastric carcinoma [18] .…”

Section: Yu Lz Et Al Expression Of Cox-2 Proteins In Gastric Mucosalmentioning

confidence: 99%

Expression of COX-2 proteins in gastric mucosal lesions

Yu¹,

Gao²,

Bai³

et al. 2004

WJG

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AIM:To investigate the expression of COX-2 proteins in gastric mucosal lesions and to assess the relationship between COX-2 expression and type, pathologic stage, differentiation, or lymph node metastasis in gastric cancer and the relationship between COX-2 expression and H pylori infection in gastric mucosal lesions. METHODS:Thirty patients with gastric carcinoma underwent surgical resection. Samples were taken from tu mor si te and pa rac anc er ous ti ssu es, an d A BC immunohistochemical staining was used to detect the expression of COX-2 proteins. H pylori was determined by rapid urea test combined with pathological stating/ 14 C urea breath test. RESULTS:The positive rate and staining intensity of mutant COX-2 gene expression in gastric cancer were significantly higher than those in paracancerous tissues (66.7% vs 26.7%) (P<0.01, P<0.001). There was a significant correlation between COX-2 and pathologic stage or lymph node metastasis type of gastric carcinoma (76.0% vs 20.0%, 79.2% vs 16.7%) (P<0.05). No correlation was found between COX-2 expression and type or grade of differentiation (P>0.05). COX-2 expression of intestinal metaplasia (IM) or dysplasia (DYS) with positive H pylori was significantly higher than that with negative H pylori (50.6% vs 18.1%, 60.0% vs 33.3%) (P<0.05).CONCLUSION: COX-2 overexpression was found in a large proportion of gastric cancer tissues compared with matched non-cancerous tissues and was significantly associated with advanced tumor stage and lymph node metastasis. Overexpression of COX-2 plays an important role in tumor progression of gastric cancer. COX-2 may also play a role in the early development/promotion of gastric carcinoma and is associated with H pylori infection. INTRODUCTIONRecently, a number of researches show that COX-2 was expressed at a very high level in gastrointestinal tumors. However, we know less about COX-2 expression in gastric cancer, especially the relationship between COX-2 overexpression and typing, degree, differentiation, lymphonic metastasis of gastric cancer. In this paper, we investigated the expression of COX-2 proteins in gastric mucosal lesions and assessed the relationship between COX-2 expression and the type, pathologic stage, differentiation, or lymph node metastasis in gastric cancer and the relationship between expression of COX-2 and H pylori infection in gastric mucosal lesions.

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“…Cyclooxygenase is a key enzyme that catalyses the conversion of prostaglandins and other eicosanoids from arachidonic acid. COX-2 is induced during pathologic conditions and is often overexpressed in premalignant lesions and malignant tumors [3,6,24,43,44]. This enzyme is linked to carcinogenesis, maintenance of progressive tumor growth, and facilitation of metastatic spread [4,41].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicate that COX-2, an enzyme involved in the metabolic conversion of arachidonic acid to prostaglandins, plays an important role in tumor growth and spread of established tumors by affecting mitogenesis, cellular adhesion, immune surveillance, apoptosis, and angiogenesis [6,21,24,34,44,41,46]. Several studies have shown that COX-2 expression is elevated in human colorectal neoplasia as compared to normal mucosa, thus making COX-2 a potential target for chemoprevention [7,15,42].…”

Section: Introductionmentioning

confidence: 99%

The role of COX-2 in rectal cancer treated with preoperative radiotherapy

et al. 2008

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Radiotherapy is one of the principal modalities of rectal cancer treatment, and the ability to predict radio resistance could potentially improve survival through a targeted treatment approach. Cyclooxygenase-2 (COX-2) may protect against damage by irradiation that would justify the use of COX-2 inhibitors. The purpose of this study was to investigate the potential role of COX-2 in tumor response and outcome of patients with rectal cancer treated preoperatively with radiotherapy. Using immunohistochemistry, we examined COX-2 expression in 88 surgical specimens of rectal cancer treated preoperatively and in 26 pretherapeutic biopsies. We tested whether COX-2 expression was correlated with clinico-pathologic parameters and with survival and local recurrence. COX-2 was expressed in 50% of the pretherapeutic tumor biopsies and in 88.6% of post-irradiated surgical samples. COX-2 expression was correlated only with enhanced tumor inflammation (p=0.03) and with tumor volume exceeding 30 cc (p=0.05). COX-2 was not significantly correlated with patient survival, but none of the patients with COX-2 negative tumors did recur locally, whereas 80% of patients with local recurrences have COX-2 positive tumors. We conclude that COX-2 expression is overexpressed in the majority of rectal cancers treated with radiotherapy and likely plays a role in local relapse.

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Effect of Helicobacter pylori‐Induced Cyclooxygenase‐2 on Gastric Epithelial Cell Kinetics: Implication for Gastric Carcinogenesis

Abstract: The expression of COX-2 is associated with disruption in gastric epithelial kinetics and hence may play a role in gastric carcinogenesis.

Cited by 35 publications

References 45 publications

Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation

Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation

Expression of COX-2 proteins in gastric mucosal lesions

The role of COX-2 in rectal cancer treated with preoperative radiotherapy

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