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SIX1 promotes epithelial–mesenchymal transition in colorectal cancer through ZEB1 activation

Oncogene volume 31, pages 4923–4934 (2012)Cite this article

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Abstract

Epithelial–mesenchymal transition (EMT) has a major role in cancer progression, as well as normal organ development and human pathology such as organ fibrosis and wound healing. Here, we performed a gene expression array specialized in EMT of colorectal cancer (CRC). From a comprehensive gene expression analysis using epithelial- and mesenchymal-like CRC cell lines, and following the ontology (GO) analysis, SIX1 gene was identified to be an EMT-related gene in CRC. Using SW480 cells stably transfected with a SIX1 expression construct and their control counterparts, we demonstrated that SIX1 overexpression represses CDH1 expression and promotes EMT in CRC. SIX1-induced CDH1 repression and EMT in CRC cells were correlated at least in part with posttranscriptional ZEB1 activation and miR-200-family transcriptional repression. In primary tumors of CRC, in accord with the functional findings, aberrant expression of SIX1 in cancer cells was observed at the disruption of the basement membrane and at the tumor invasive front, where tumor cells underwent EMT in vivo. Taken together, SIX1 overexpression is suggested to occur in carcinogenesis, and contribute to repression of CDH1 expression and promotion of EMT partly through repression of miR-200-family expression and activation of ZEB1 in CRC.

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Acknowledgements

This study was supported by grants-in-aid for Scientific Research (A), (B) (C) and on Priority Areas, and the Global Center of Excellence (GCOE) Program; International Research Center for Molecular Science in Tooth and Bone Diseases from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan; and a grant from the New Energy and Industrial Technology Development Organization (NEDO). We thank Yoko Takagi, Ayako Takahashi, Rumi Mori and Kathy Masker for technical assistance.

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Authors and Affiliations

  1. Department of Molecular Cytogenetics, Tokyo Medical and Dental University, Tokyo, Japan

    H Ono, I Imoto, K Kozaki, Y Kurasawa, T Muramatsu & J Inazawa

  2. Department of Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

    H Ono & K Sugihara

  3. Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    I Imoto

  4. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan

    H Tsuda

  5. Medical Top Track Program, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan

    T Matsui

  6. Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan

    J Inazawa

  7. Global Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan

    J Inazawa

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  1. H Ono
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Correspondence to J Inazawa.

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Ono, H., Imoto, I., Kozaki, K. et al. SIX1 promotes epithelial–mesenchymal transition in colorectal cancer through ZEB1 activation. Oncogene 31, 4923–4934 (2012). https://doi.org/10.1038/onc.2011.646

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