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Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion

Oncogene volume 37, pages 651–662 (2018)Cite this article

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Abstract

Hypoxia is a driver of cell movement in processes such as development and tumor progression. The cellular response to hypoxia involves a transcriptional program mediated by hypoxia-inducible factors, but translational control has emerged as a significant contributor. In this study, we demonstrate that a cell–cell adhesion molecule, cadherin-22, is upregulated in hypoxia via mTORC1-independent translational control by the initiation factor eIF4E2. We identify new functions of cadherin-22 as a hypoxia-specific cell-surface molecule involved in cancer cell migration, invasion and adhesion. Silencing eIF4E2 or cadherin-22 significantly impaired MDA-MB-231 breast carcinoma and U87MG glioblastoma cell migration and invasion only in hypoxia, while reintroduction of the respective exogenous gene restored the normal phenotype. Cadherin-22 was evenly distributed throughout spheroids and required for their formation and support of a hypoxic core. Conversely, E-cadherin translation was repressed by hypoxia and only expressed in the oxygenated cells of U87MG spheroids. Furthermore, immunofluorescence on paraffin-embedded human tissue from 40 glioma and 40 invasive ductal breast carcinoma patient specimens revealed that cadherin-22 expression colocalized with areas of hypoxia and significantly correlated with tumor grade and progression-free survival or stage and tumor size, respectively. This study broadens our understanding of tumor progression and metastasis by highlighting cadherin-22 as a potential new target of cancer therapy to disable hypoxic cancer cell motility and adhesion.

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Acknowledgements

We thank Terry Van Raay for the use of his microscope, Scott Ryan and John Vessey for the use of their cryostat, and Marc Coppolino for technical advice and reagents. This work was funded by grants from the Canadian Institutes of Health Research (PJT 152925) and the Cancer Research Society to JU.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada

    N J Kelly, J F A Varga, E J Specker, C M Romeo & J Uniacke

  2. Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada

    B L Coomber

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Correspondence to J Uniacke.

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Kelly, N., Varga, J., Specker, E. et al. Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion. Oncogene 37, 651–662 (2018). https://doi.org/10.1038/onc.2017.372

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