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HST-1/FGF-4 plays a critical role in crypt cell survival and facilitates epithelial cell restitution and proliferation

Oncogene volume 23, pages 3681–3688 (2004)Cite this article

Abstract

The fibroblast growth factor-4 (HST-1/FGF-4) is a heparin-binding growth factor that influences on epithelial and many other cells through interaction with FGF receptors. It has been demonstrated that the HST-1/FGF-4 gene protects mice from lethal irradiation by preventing bone marrow damage and intestinal tract damage. However, the radioprotective mechanism is unknown. In this study, we have investigated the expression of Hst-1/Fgf-4 in mouse small intestine after irradiation, and determined the role of HST-1/FGF-4 in mouse intestinal crypt cell survival and epithelial cell proliferation and restitution. We found the induction of endogenous Hst-1/Fgf-4 expression in intestine when mice are exposed to 9.0 Gy irradiation. Laser-captured microdissection (LCM) coupled with RT–PCR analysis revealed that expression of Hst-1/Fgf-4 was found in epithelial cell of the villi and crypt cells. Pretreatment of HST-1/FGF-4 caused an increase in the number of surviving crypt cells, and clearly suppresses the radiation-induced apoptosis of the crypt cells. Moreover, exogenous HST-1/FGF-4 enhances epithelial cell restitution and proliferation in an in vitro model. These data suggest that HST-1/FGF-4 is induced by irradiation injury, and that HST-1/FGF-4 will find a therapeutic role in the prevention of intestinal cell toxicity following intensive chemotherapy and radiation therapy protocols, and in allogenic cell transplantation.

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Acknowledgements

We gratefully acknowledge Dr Hiroyuki Daiko (Genetics Division, National Cancer Center Institute, Japan) for kind assistance. We thank Ms Masako Hosoda, Ms Kaoru Yoshida, and Ms Kazumi Kimura for their excellent technical work. This work was supported in part by a Grant-Aid for the Second-Term Comprehensive 10-Year Strategy for Cancer Control, Health Science Research Grants for the Research on Human Genome and Gene Therapy from the Ministry of Health, Labour, and Welfare of Japan, and Gene Therapy from the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid by Japan Owner's association.

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  1. Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuoku, Tokyo, 104-0045, Japan

    Hideo Sasaki, Kotaro Hirai, Hanako Yamamoto & Takahiro Ochiya

  2. National Institute of Radiological Science, 4-9-1, Anagawa, Inage-ku, Chiba, 263-8555, Japan

    Hiroshi Tanooka

  3. Genetics Division, National Cancer Research Institute, 1-1, Tsukiji, 5-chome, Chuoku, Tokyo, 104-0045, Japan

    Hiromi Sakamoto & Masaaki Terada

  4. Department of Urology, St. Marianna University School of Medicine, 2-16-1, Sugao 2-chome, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan

    Hideo Sasaki, Teruaki Iwamoto & Takeshi Takahashi

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  1. Hideo Sasaki
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Correspondence to Takahiro Ochiya.

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Sasaki, H., Hirai, K., Yamamoto, H. et al. HST-1/FGF-4 plays a critical role in crypt cell survival and facilitates epithelial cell restitution and proliferation. Oncogene 23, 3681–3688 (2004). https://doi.org/10.1038/sj.onc.1207348

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