Effects of selective COX-2 inhibitor and<i>Helicobacter pylori</i>eradication on precancerous gastric lesions

Wong, Benjamin Chun–Yu; Zhang, Lian; Ma, Junling; Pan, Kai; Li, Jiyou; Shen, Lin; Liu, Weidong; Feng, Guoshuang; Zhang, Xiaodong; Li, Jie; Lü, Aiping; Xia, Harry H.X.; Lam, Shiu‐Kum; You, Wei‐Cheng

doi:10.1136/gutjnl-2011-300154

Cited by 139 publications

(164 citation statements)

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“…5 Selective cyclooxygenase-2 (COX-2) inhibitors have beneficial effects on preventing inflammation-related carcinogenesis and on the regression of advanced GC. 6,7 COX-2 induces the production of PGE 2 , which upregulates NR4A2 expression via sequential activation of the Rho, protein kinase A (PKA), and nuclear factor-jB signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy

Han

Cai

et al. 2013

Cancer

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BACKGROUND: NR4A2, an orphan nuclear receptor essential in the generation of dopaminergic neurons, has been recently linked to inflammation and cancer. This study sought to identify the role of NR4A2 on chemoresistance and postoperative prognosis of gastric cancer (GC). METHODS: NR4A2 was transfected into GC cells to investigate its effects on chemoresistance to 5-fluorouracil and the tumorigenicity in nude mice. This study also investigated prostaglandin E2 (PGE 2 )-induced NR4A2 expression and its effect on chemoresistance. Surgical specimens from patients with stage I through III GC were examined immunohistochemically for NR4A2 expression. Median follow-up time was 76 months for 245 patients. RESULTS: Ectopic expression of NR4A2 significantly increased the chemoresistance and attenuated 5-fluorouracil-induced apoptosis. Transient treatment of GC cells with PGE 2 significantly upregulated NR4A2 expression via the protein kinase A pathway and increased the chemoresistance. Ectopic expression of NR4A2 significantly increased the tumorigenicity. In clinical samples, NR4A2 was preferentially expressed in lymphocytes and epithelial cytoplasm in adjacent mucosa. High expression of NR4A2 (immunoreactive score 3) in cancer cells significantly predicted an unfavorable postoperative disease-specific survival of patients with stage I to III GC (P 5.011), especially for those who received 5-fluorouracil-based chemotherapy (P 5.016). This effect was not found in those without the chemotherapy. In multivariate Cox analyses, age, TNM (tumor/node/metastasis) stage, and high NR4A2 expression significantly predicted an unfavorable postoperative survival. CONCLU-SIONS: High NR4A2 expression in GC cells confers chemoresistance, attenuates 5-fluorouracil-induced apoptosis, and predicts an unfavorable survival, especially for those who received chemotherapy. NR4A2 might serve as a prognostic and predictive factor and therapeutic target for patients with GC. Cancer 2013;119:3436-45.

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Section: Introductionmentioning

confidence: 99%

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy

Han

Cai

et al. 2013

Cancer

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“…27). A recent subgroup analysis indicated that the elimination of H. pylori can reduce gastric cancer incidence in older participants and in those with advanced baseline histopathology (28). From 2002 to 2006, another randomized, placebo-controlled trial was conducted in Linqu to study the effects of H. pylori eradication and a COX-2 inhibitor (celecoxib) in a 2 Â 2 factorial design with 1,024 participants (29).…”

Section: Studies On Etiology and Prevention Of Gastric Cancer In Linqmentioning

confidence: 99%

Cancer Prevention Research in China

Yang

et al. 2015

Cancer Prevention Research

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“…In 2004, a total of 1,024 eligible participants were invited to the intervention trial according to the selection and exclusion criteria described previously (24). Briefly, the trial included participants ages 35-64 years with H. pylori-positive and baseline histology of chronic atrophic gastritis, intestinal metaplasia, indefinite dysplasia, or dysplasia.…”

Section: Study Populationmentioning

confidence: 99%

“…In 2002, an initial screening program was conducted in Linqu County, a high-risk area of gastric cancer in China, with interview, carbon-13 urea breath test ( 13 C-UBT), upper endoscopy and pathologic diagnosis (24). In 2004, a total of 1,024 eligible participants were invited to the intervention trial according to the selection and exclusion criteria described previously (24).…”

Section: Study Populationmentioning

confidence: 99%

“…From 2002 to 2006, we conducted an intervention trial in Linqu (Linqu Intervention Trial) using anti-H. pylori and/or selective COX-2 inhibitor (celecoxib; ref. 24), and found that COX-2 expression and its interaction with H. pylori infection were associated with the evolutions of gastric lesions (25). Whether the COX-2 methylation is one of the mechanisms for the effect of interventions still needs further investigation.…”

Section: Introductionmentioning

confidence: 99%

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Alterations of Cyclooxygenase-2 Methylation Levels Before and After Intervention Trial to Prevent Gastric Cancer in a Chinese Population

Zhang

Zeng

Nie

et al. 2016

Cancer Prevention Research

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To explore the epigenetic mechanisms underlying the effects of anti-Helicobacter pylori (H. pylori) alone and combined with COX-2 inhibitor (celecoxib), we dynamically evaluated the associations between COX-2 methylation alterations and gastric lesion evolution during the process of interventions. In a total of 809 trial participants COX-2 methylation levels were quantitatively detected before and after treatment. The self-comparison at the same stomach site for each subject showed significant methylation alteration differences among intervention groups (P < 0.001). With placebo group as reference, COX-2 methylation levels were decreased in anti-H. pylori [OR, 3.30; 95% confidence interval (CI), 2.16-5.02], celecoxib (OR, 2.04; 95% CI, 1.36-3.07), and anti-H. pylori followed by celecoxib (OR, 2.10; 95% CI, 1.38-3.17) groups. When stratified by baseline histology, the three active arms significantly decreased COX-2 methylation levels in indefinite dysplasia/dysplasia subjects, and ORs were 3.65 (95% CI, 1.96-6.80) for anti-H. pylori, 2.43 (95% CI 1.34-4.39) for celecoxib, and 2.80 (95% CI, 1.52-5.15) for anti-H. pylori followed by celecoxib, respectively. No additive effect on COX-2 methylation was found for anti-H. pylori followed by celecoxib than two treatments alone. Compared with subjects without methylation reduction, higher opportunity for gastric lesion regression was found in subjects with decreased COX-2 methylation levels, especially for indefinite dysplasia/dysplasia subjects (OR, 1.92; 95% CI, 1.03-3.60). These findings suggest that anti-H. pylori or celecoxib treatment alone could decrease COX-2 methylation levels in gastric mucosa. COX-2 methylation alteration was associated with the regression of indefinite dysplasia/dysplasia, which might serve as a potential biomarker for chemoprevention efficacy. Cancer Prev Res; 9(6); 484-90. Ó2016 AACR.

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Effects of selective COX-2 inhibitor andHelicobacter pylorieradication on precancerous gastric lesions

Cited by 139 publications

References 31 publications

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy

Cancer Prevention Research in China

Alterations of Cyclooxygenase-2 Methylation Levels Before and After Intervention Trial to Prevent Gastric Cancer in a Chinese Population

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