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

A. Ooki, K. Yamashita, S. Kikuchi, S. Sakuramoto, N. Katada, K. Kokubo, H. Kobayashi, M. S. Kim, D. Sidransky, M. Watanabe

Research output: Contribution to journalArticle

Abstract

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 (P0.0001). 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 (P0.029) 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.

Original languageEnglish (US)
Pages (from-to)3263-3275
Number of pages13
JournalOncogene
Volume29
Issue number22
DOIs
StatePublished - Jun 3 2010

Keywords

  • Gastric cancer
  • HOP homeobox
  • Methylation
  • Prognosis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Ooki, A., Yamashita, K., Kikuchi, S., Sakuramoto, S., Katada, N., Kokubo, K., Kobayashi, H., Kim, M. S., Sidransky, D., & Watanabe, M. (2010). Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer. Oncogene, 29(22), 3263-3275. https://doi.org/10.1038/onc.2010.76