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GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-β-dependent apoptotic signalling

Oncogene volume 26, pages 6488–6498 (2007)Cite this article

Abstract

Defining apoptosis-regulatory cascades of the epithelium is important for understanding carcinogenesis, since cancer cells are considered to arise as a result of the collapse of the cascades. We previously reported that a novel gene GASDERMIN (GSDM) is expressed in the stomach but suppressed in gastric cancer cell lines. Furthermore, in this study, we demonstrated that GSDM is expressed in the mucus-secreting pit cells of the gastric epithelium and frequently silenced in primary gastric cancers. We found that GSDM has a highly apoptotic activity and its expression is regulated by a transcription factor LIM domain only 1 (LMO1) through a sequence to which Runt-related transcription factor 3 (RUNX3) binds, in a GSDM promoter region. We observed coexpression of GSDM with LMO1, RUNX3 and type II transforming growth factor -β receptor (TGF-βRII) in the pit cells, and found that TGF-β upregulates the LMO1- and GSDM-expression in the gastric epithelial cell line and induces apoptosis, which was confirmed by the finding that the apoptosis induction is inhibited by suppression of each LMO1-, RUNX3- and GSDM expression, respectively. The present data suggest that TGF-β, LMO1, possibly RUNX3, and GSDM form a regulatory pathway for directing the pit cells to apoptosis.

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Acknowledgements

This work was supported in part by the program for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio), in part by a grant-in-aid for the third comprehensive 10-year strategy for cancer control and for cancer research (15–15, 16–15) from the Ministry of Health and Welfare of Japan, and in part by a research grant of the Princess Takamatsu Cancer Research Fund.

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Author notes

  1. N Saeki and D H Kim: These two authors contributed equally to this work.

Authors and Affiliations

  1. Center for Medical Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

    N Saeki, H Mizushima, M Ohki & T Yoshida

  2. Genetics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

    N Saeki, D H Kim, T Usui, K Aoyagi, T Tatsuta, H Sakamoto, T Yoshida & H Sasaki

  3. Medical Center East, School of Medicine, Tokyo Women's Medical University, Arakawa-ku, Tokyo, Japan

    D H Kim, T Usui & K Ogawa

  4. Section for Studies on Host-immune Response, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

    K Aoki

  5. Central Animal Laboratory, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

    K Yanagihara

  6. Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka, Japan

    M Tamura & T Shiroishi

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  1. N Saeki
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Correspondence to H Sasaki.

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Saeki, N., Kim, D., Usui, T. et al. GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-β-dependent apoptotic signalling. Oncogene 26, 6488–6498 (2007). https://doi.org/10.1038/sj.onc.1210475

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