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

Oncogene volume 29, pages 3263–3275 (2010)Cite this article

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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 (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.

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Acknowledgements

This work was supported, in part, by the Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan and by the Japanese Foundation for Multidisciplinary Treatment of Cancer.

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Authors and Affiliations

  1. Department of Surgery, Kitasato University Hospital, Sagamihara, Kanagawa, Japan

    A Ooki, K Yamashita, S Kikuchi, S Sakuramoto, N Katada & M Watanabe

  2. Department of Medical Engineering and Technology, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan

    K Kokubo & H Kobayashi

  3. Department of Otolaryngology, Head and Neck Cancer Research Institute, Johns Hopkins University, Baltimore, MD, USA

    M S Kim & D Sidransky

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  1. A Ooki
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  2. K Yamashita
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Correspondence to A Ooki or M Watanabe.

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Ooki, A., Yamashita, K., Kikuchi, S. et al. Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer. Oncogene 29, 3263–3275 (2010). https://doi.org/10.1038/onc.2010.76

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