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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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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DOI: https://doi.org/10.1038/sj.onc.1210475
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