Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer

• Published in: Oncogene Vol. 29; no. 22; pp. 3263 - 3275
• Main Authors: Ooki, A, Yamashita, K, Kikuchi, S, Sakuramoto, S, Katada, N, Kokubo, K, Kobayashi, H, Kim, M S, Sidransky, D, Watanabe, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.06.2010; Nature Publishing Group
• Subjects: 631/67/1857; 692/699/67/1504/1829; Apoptosis; Biological and medical sciences; Bisulfite; Cell Biology; Cell Growth Processes - genetics; Cell Line, Tumor; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cohort Studies; CpG Islands; DNA damage; DNA Methylation; Fundamental and applied biological sciences. Psychology; Gastric cancer; Gastroenterology; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Homeobox; Genetic aspects; Homeobox; Homeobox genes; Homeodomain Proteins - genetics; Homeotic genes; Human Genetics; Humans; Immunohistochemistry; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Molecular and cellular biology; Multivariate analysis; Neoplasm Invasiveness; Oncology; original-article; Physiological aspects; Polymerase chain reaction; Prognosis; Promoter Regions, Genetic; Promoters (Genetics); Stomach cancer; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcription; Tumor cell lines; Tumor Suppressor Proteins - genetics; Tumors; United States; gastric cancer; prognosis; methylation; HOP homeobox; Prognosis; Homeotic gene; Digestive diseases; Malignant tumor; Methylation; Stomach cancer; Carcinogenesis; Cancer; Gastric disease; Aggressiveness
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.76

HOP homeobox ( HOPX ) is an unusual homeobox gene encoding three spliced transcript variants, among which the only HOPX-β promoter harbors CpG islands. The characteristics of its promoter methylation was analyzed using bisulfite sequencing and quantitative-methylation-specific polymerase chain reaction (Q-MSP), and the effects of HOPX expression were also examined. HOPX-β expression was silenced in all gastric cancer cell lines tested; its expression could be restored by treatment with demethylating agent. On Q-MSP, HOPX-β hypermethylation (cut-off value of 3.55) was found in 84% (67 out of 80) of primary tumor tissues and 10% (8 out of 80) of the corresponding normal tissues and could discriminate normal from tumor tissues ( P <0.0001). The prognosis of the advanced cases with HOPX-β hypermethylation was as poor as those with stage IV disease when cut-off value was set at 11.28. This finding was validated in an independent cohort of 90 advanced gastric cancers. The HOPX-β hypermethylation was also an independent prognostic factor ( P =0.029) on multivariate analysis. Exogenous HOPX expression significantly inhibited cell proliferation, colony formation and invasion as well as enhanced apoptosis. Taken together, HOPX-β promoter methylation is a frequent and cancer-specific event in gastric cancer. Quantitative assessment of HOPX-β methylation has great clinical potential as a marker of tumor aggressiveness.