The −251T Allele of the Interleukin-8 Promoter Is Associated with Increased Risk of Gastric Carcinoma Featuring Diffuse-Type Histopathology in Chinese Population

• Published in: Clinical cancer research Vol. 11; no. 18; pp. 6431 - 6441
• Main Authors: LEE, Wei-Ping, TAI, Dar-In, CHAO, Yee, YEN, Shang-Heu, LEE, Shou-Dong, LAN, Keng-Hsin, LI, Anna Fen-Yau, HSU, Hou-Ching, LIN, En-Ju, LIN, Yi-Ping, SHEU, Meei-Ling, LI, Chung-Pin, CHANG, Full-Young
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2005
• Subjects: Adult; Aged; Alleles; Antineoplastic agents; Base Sequence; Biological and medical sciences; Case-Control Studies; Cell Line, Tumor; Chi-Square Distribution; China; Female; gastric cancer; Gastroenterology. Liver. Pancreas. Abdomen; Gene Frequency; Genotype; Helicobacter Infections - genetics; Helicobacter Infections - microbiology; Helicobacter pylori; Humans; Interleukin-8; Interleukin-8 - genetics; Male; Medical sciences; Middle Aged; Odds Ratio; Pharmacology. Drug treatments; polymorphism; Polymorphism, Single Nucleotide; Promoter Regions, Genetic - genetics; Risk Factors; Stomach Neoplasms - genetics; Stomach Neoplasms - microbiology; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumor Cells, Cultured; Tumors; Asia; China; Human; Angiogenic factor; Transcription promoter; Cytokine; Risk; Malignant tumor; Epidemiology; Stomach carcinoma; Allele; Anatomic pathology; Histopathology; Risk factor; Digestive diseases; Chinese; Genetics; Interleukin 8; Gastric disease
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0942

Purpose: Persistent interleukin-8 (IL-8) production contributes to chronic inflammation of the stomach. The proinflammatory IL-1β polymorphisms, which enhance the cytokine production, are associated with increased risk of gastric cancer. The −251A/T polymorphism of the IL-8 promoter is involved in several human diseases. Particularly, the −251A is associated with decreased risk of colorectal cancer. We aimed to determine whether the −251 allele resulting in high IL-8 expression was associated with increased risk of gastric carcinoma. Experimental Design: The −251A/T promoters were cloned and analyzed by luciferase assay. Binding of nuclear proteins to the −251A/T promoters was analyzed by electrophoretic mobility shift assay. The −251A/T promoters were differentiated by PCR-RFLP. Comparison of gastric cancer risk between the −251A/T promoters was done by a case-control study. Results: The −251T allele possessed transcriptional activity 2- to 5-fold stronger than the −251A counterpart. Electrophoretic mobility shift assay showed that the −251A promoter had strong ability to bind to an unknown protein or multiprotein complex. The −251T allele was associated with increased risk of noncardia ( P trend = 0.012) and cardia ( P trend = 0.029) carcinomas. Gastric carcinoma patients with the low-risk AA genotype had a tendency to sustain intestinal-type carcinomas (χ 2 = 6.816; P = 0.033); however, the high-risk −251T allele was associated with >2-fold increased risk of diffuse-type (AA versus AT + TT: odds ratio, 2.52; 95% confidence interval, 1.16-5.49; P = 0.017) and mixed-type (AA versus AT + TT: odds ratio, 2.22; 95% confidence interval, 1.12-4.40; P = 0.019) carcinomas. Conclusions: The IL-8 −251T allele is significantly associated with increased risk of gastric carcinoma, particularly the diffuse and mixed types in Chinese population.