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ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation

Oncogene volume 24, pages 8051–8060 (2005)Cite this article

Abstract

Array-based comparative genomic hybridization (CGH-array) has a powerful potential for high-throughput identification of genetic aberrations in cell genomes. We identified a homozygous loss of ADAM23 (2q33.3) in the course of a program to screen a panel of gastric cancer (GC) cell lines (1/32, 3.1%) for genomic copy-number aberrations using our custom-made CGH-array. Infrequent homozygous deletion of ADAM23 was also seen in primary gastric tumors (1/39, 2.6%). ADAM23 mRNA was expressed in normal stomach tissue, but not in the majority of GC cell lines without homozygous deletion of this gene. Expression of ADAM23 mRNA was restored to gene-silenced GC cells after treatment with 5-aza 2′-deoxycytidine. The methylation status of the ADAM23 CpG island, which showed promoter activity, correlated inversely with its expression. Methylation of this CpG island was observed both in GC cell lines and in primary GC tissues; in primary tumors with a hypermethylated CpG island, expression of ADAM23 was lower than in adjacent noncancerous tissues. Moreover, restoration of ADAM23 in GC cells reduced their numbers in colony-formation assays. These results suggest that genetic or epigenetic silencing by hypermethylation of the ADAM23 CpG-rich promoter region leads to loss of ADAM23 function, which may be a factor in gastric carcinogenesis.

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Acknowledgements

We are grateful to Professor Yusuke Nakamura (Human Genome Center, The Institute of Medical Science, The University of Tokyo) for his continuous encouragement throughout this work. We thank Professor Jae-Gahb Park (Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine) and Dr Kazuyoshi Yanagihara (Central Animal Laboratory, National Cancer Center Research Institute) for providing GC cell lines and Ai Watanabe for technical assistance.

This work was supported by Grants-in-Aid for Scientific Research on Priority Areas (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan; by a Grant-in-Aid from Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Corporation (JST); by a Center of Excellence (COE) program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone; by the program for promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA); and by the Third Term Comprehensive Control Research for Cancer of the Ministry of Health, Labour and Welfare.

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Authors and Affiliations

  1. Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    Hisashi Takada, Issei Imoto & Johji Inazawa

  2. Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation (JST), Hon-machi Kawaguchi, Saitama, Japan

    Hisashi Takada, Issei Imoto, Hitoshi Tsuda, Fumie Hosoda & Johji Inazawa

  3. Division of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji Kamigyo-ku, Kyoto, Japan

    Hisashi Takada & Shoji Mitsufuji

  4. Department of Pathology II, National Defense Medical College, Namiki, Tokorozawa, Japan

    Hitoshi Tsuda

  5. Pathology Division, National Cancer Center Research Institute, Tsukiji Chuo-ku Tokyo, Japan

    Yukihiro Nakanishi & Setsuo Hirohashi

  6. Department of Surgery I, National Defense Medical College, Namiki, Tokorozawa, Japan

    Takashi Ichikura & Hidetaka Mochizuki

  7. Cancer Genomics Project, National Cancer Center Research Institute, Tsukiji Chuo-ku Tokyo, Japan

    Fumie Hosoda & Misao Ohki

  8. COE program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    Johji Inazawa

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  1. Hisashi Takada
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Takada, H., Imoto, I., Tsuda, H. et al. ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation. Oncogene 24, 8051–8060 (2005). https://doi.org/10.1038/sj.onc.1208952

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