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Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia

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Abstract

Purpose

The molecular mechanisms underlying the development of intestinal metaplasia (IM) of the human stomach have yet to be clarified in detail. Besides ectopic expression of intestinal transcription factors, Cdx1 and Cdx2, little information is available regarding other regulatory factors. Hence, we here analyzed Sox2, a human homolog of a chicken gastric transcription factor, with reference to our new classification for gastric/intestinal (GI)-mixed type IM.

Methods

Twenty specimens of surgically resected antral mucosa were subjected to a gland isolation technique. Isolated glands were classified into gastric (G), GI-mixed, and solely intestinal (I) types according to Alcian blue and paradoxical concanavalin A staining and were quantified for mRNA levels of gastrointestinal markers.

Results

MUC5AC and MUC6 transcripts decreased with the progression of IM, while MUC2 and villin-1 were inversely correlated. Sox2 showed a gradual decrease from G, through GI, to the I type (G vs GI and GI vs I, P<0.01 and P<0.005, respectively). On the other hand, Cdx1 (G vs GI and GI vs I, P<0.0001 and P=0.337, respectively) and Cdx2 (G vs GI and GI vs I, P<0.0001 and P<0.05, respectively) appeared in IM. Immunohistochemical study confirmed decreased expression of Sox2 and ectopic emergence of Cdx2 protein in IM glands.

Conclusion

Down-regulation of Sox2, besides ectopic expression of Cdx genes, may be important factors for the development of IM.

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Acknowledgments

The authors thank Ms. Naoko Ban and Ms. Rika Haruta for expert technical assistance. This study was supported in part by a Research Grant from the Princess Takamatsu Cancer Research Fund (00–23207), a Grant-in-Aid for the Millennium Genome Project, a Grant-in-Aid for the Second-term Comprehensive 10-year Strategy for Cancer Control, and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan, and a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Nagoya, Chikusa-ku, Japan

    Tetsuya Tsukamoto, Kenichi Inada, Harunari Tanaka, Tsutomu Mizoshita & Masae Tatematsu

  2. Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan

    Mami Mihara & Toshikazu Ushijima

  3. Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan

    Yoshitaka Yamamura

  4. Department of Pathology and Clinical Laboratories, Aichi Cancer Center Hospital, Nagoya, Japan

    Shigeo Nakamura

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  1. Tetsuya Tsukamoto
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  2. Kenichi Inada
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Correspondence to Tetsuya Tsukamoto.

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Tsukamoto, T., Inada, K., Tanaka, H. et al. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia. J Cancer Res Clin Oncol 130, 135–145 (2004). https://doi.org/10.1007/s00432-003-0519-6

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