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Integrin α9β1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition

Oncogene volume 32, pages 141–150 (2013)Cite this article

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Abstract

The integrin α9β1 binds a number of extracellular matrix components to mediate cell adhesion, migration and tissue invasion. Although expressed in a variety of normal human cells including endothelium, it is also expressed in cancer cells. We have previously shown that α9β1 binds VEGF-A to facilitate angiogenesis, an important component of the tumor microenvironment. As α9β1 induces accelerated cancer cell migration, we wished to determine what role it played in cancer growth and metastasis. In this study, we show that α9β1 expression induces molecular changes consistent with epithelial-mesenchymal transition. In addition, we found that α9β1 forms a tri-partite protein complex with β-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and β-catenin phosphorylation. These findings were consistent in cells in which: α9β1 was exogenously over-expressed, or when its expression was suppressed in cancer cells endogenously expressing α9β1. These in vitro results are biologically significant as α9β1-expressing cancer cells induce greater tumor growth and metastases in mice as compared to the cells without α9β1 expression or when integrin expression is suppressed. Furthermore, integrin α9β1 is expressed in primary human small cell lung cancer and patients having a high expression of α9β1 demonstrated significantly worse long-term survival compared with patients with low α9β1 expression. These findings highlight a novel mechanism of integrin α9β1 function in human cancer.

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Acknowledgements

We thank Drs Dean Sheppard (UCSF, CA), Debabrata Mukhopadhyay and Edward Leof (Mayo Clinic, Rochester, MN, USA) for helpful discussions; Mark A. Schroeder for help with animal studies; Aaron Bungam for the lung tissue registry. This work was supported by NHLBI Research Grant K08HL076455-05 and Mayo Foundation Research Grants to NEV.

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Authors and Affiliations

  1. Division of Pulmonary & Critical Care Medicine, Thoracic Disease Research Unit, Mayo Clinic, Rochester, MN, USA

    S K Gupta, S Oommen, B P Williams & N E Vlahakis

  2. Department of Laboratory Medicine and Anatomic Pathology, Mayo Clinic, Rochester, MN, USA

    M-C Aubry

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  1. S K Gupta
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Correspondence to N E Vlahakis.

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Gupta, S., Oommen, S., Aubry, MC. et al. Integrin α9β1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition. Oncogene 32, 141–150 (2013). https://doi.org/10.1038/onc.2012.41

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