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Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

Oncogene volume 30, pages 1693–1705 (2011)Cite this article

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Abstract

Stem cells in normal tissues and cancer-initiating cells (CICs) are known to be enriched in side population (SP) cells. However, the factors responsible for the regulation of expression of ABCG2, involved in efflux of dyes, in SP cells have not been fully investigated. Here, we characterized the SP cells within diffuse-type gastric carcinoma, and examined the effects of transforming growth factor-β (TGF-β) on SP cells. Diffuse-type gastric carcinoma cells established from four independent patients universally contained SP cells between 1 and 4% of total cells, which displayed greater tumorigenicity than non-SP cells did. TGF-β repressed the transcription of ABCG2 through direct binding of Smad2/3 to its promoter/enhancer, and the number of SP cells and the tumor-forming ability of cancer cells were decreased by TGF-β, although ABCG2 is not directly involved in the tumor-forming ability of SP cells. Cancer cells from metastatic site expressed much higher levels of ABCG2 and included a greater percentage of SP cells than parental cancer cells did. SP cells are thus responsible for the progression of diffuse-type gastric carcinoma, and TGF-β negatively contributes to maintain the CICs within the cancer.

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Acknowledgements

We thank Dr H Miyoshi (RIKEN) for the lentivirus vector system and Dr K Yanagihara (Yasuda Women's University) for HSC-43 cells. This study was supported by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid for Young Scientists (Start-up) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan

    S Ehata, E Johansson, Y Hoshino, Y Katsuno, A Komuro, D Koinuma, M R Kano & K Miyazono

  2. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), 3-10-6 Ariake, Koto-ku, Tokyo, Japan

    S Ehata, R Katayama, S Koike & N Fujita

  3. Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan

    A Watanabe & H Aburatani

  4. Department of Surgical Oncology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, Japan

    M Yashiro & K Hirakawa

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Correspondence to K Miyazono.

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Ehata, S., Johansson, E., Katayama, R. et al. Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells. Oncogene 30, 1693–1705 (2011). https://doi.org/10.1038/onc.2010.546

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