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Contribution of sialidase NEU1 to suppression of metastasis of human colon cancer cells through desialylation of integrin β4

Oncogene volume 28, pages 1218–1229 (2009)Cite this article

Abstract

We previously found an inverse relationship between sialidase Neu1 expression and metastatic potential of murine cancer cells. To elucidate the mechanism underlying the cellular events, the human sialidase gene NEU1 was overexpressed or silenced in colon cancer HT-29 cells. When NEU1-overexpressing cells were injected transsplenically into mice, in vivo liver metastasis was significantly reduced. NEU1 suppressed cell migration, invasion and adhesion in vitro, whereas the silencing resulted in the opposite. One of the major molecular changes by NEU1 was decreased sialylation of integrin β4, assessed by PNA- and MAL-II-lectin blotting of immunoprecipitates with anti-integrin β4 antibody. The desialylation was accompanied by decreased phosphorylation of the integrin followed by attenuation of focal adhesion kinase and Erk1/2 pathway. Moreover, NEU1 caused downregulation of matrix metalloproteinase-7, overexpression of which is associated with cancer metastasis. Treatment of the cells with GalNAc-α-O-benzyl, an inhibitor of O-glycosylation, showed increased PNA-positive integrin β4 with its decreased phosphorylation, indicating that sialic acid removal from the integrin O-glycans results in the decreased phosphorylation. Biotinylation and immunofluorescence staining exhibited some NEU1 molecules to be at the cell surface accessible to the integrin. These results suggest that NEU1 is important in regulation of integrin β4-mediated signaling, leading to suppression of metastasis.

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Acknowledgements

We appreciate the expert technical assistance of Ms Setsuko Moriya. This study was supported in part by Grants-in-Aid for Scientific Research on Priority Areas Cancer from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori, Japan

    T Uemura, K Shiozaki, K Yamaguchi, K Kato & T Miyagi

  2. CREST, JST, Kawaguchi, Japan

    T Uemura, K Shiozaki, K Yamaguchi, K Kato & T Miyagi

  3. Department of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, Sendai, Japan

    T Uemura, S Miyazaki & S Satomi

  4. Department of Analytical Biochemistry, Meiji Pharmaceutical University, Tokyo, Japan

    H Sakuraba

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  1. T Uemura
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  2. K Shiozaki
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Correspondence to T Miyagi.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Uemura, T., Shiozaki, K., Yamaguchi, K. et al. Contribution of sialidase NEU1 to suppression of metastasis of human colon cancer cells through desialylation of integrin β4. Oncogene 28, 1218–1229 (2009). https://doi.org/10.1038/onc.2008.471

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