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A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion

Oncogene volume 31, pages 2888–2898 (2012)Cite this article

Abstract

Increased activation of epidermal growth factor receptor (EGFR) family members such as HER2/Erbb2 can result in more aggressive disease, resistance to chemotherapy and reduced survival of head and neck squamous cell carcinoma (HNSCC) patients. In order to identify mechanisms through which these receptor tyrosine kinases accelerate tumor progression, the regulation of metalloprotease expression by EGFR family members was investigated in 11 squamous cell carcinoma (SCC) cell lines. HER2 expression was significantly correlated with ADAM12 (A Disintegrin And Metalloprotease 12) expression in these cell lines and was co-expressed in human head and neck cancers. Inhibition of HER2 or EGFR decreased ADAM12 transcripts whereas HER2 transfection upregulated ADAM12 expression. To understand the molecular mechanisms underlying HER2 regulation of ADAM12, we investigated the signaling pathways directing ADAM12 production in SCC cells. Inhibition of phosphatidyl inositol-3-kinase or mammalian target of rapamycin decreased ADAM12 transcripts in HER2-expressing SCC cells, whereas transfection with AKT increased ADAM12 mRNA. Experiments utilizing ADAM12 transfection or siRNA targeting of ADAM12 revealed that the protease increased both the migration and invasiveness of oral SCC cells. Surprisingly, ADAM12 also increased HER2 message, protein levels and activity through an Ets1-dependent mechanism. Collectively, these results reveal a novel positive activation loop between ADAM12 and HER2 that may contribute to HNSCC progression.

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Acknowledgements

The cell lines used in this study were gifts from Drs Greg Oakley (University of Nebraska, Lincoln) and Thomas Carey (University of Michigan). We also thank Drs U. Wewer and C. Frohlich (University of Copenhagen, Denmark) for the gifts of ADAM12 plasmids. This research was supported by the National Institutes of Health (1RO1ES015585), the State of Nebraska LB595 and The Dobleman Head and Neck Cancer Institute. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Numbers 1CO6RR17417-01 and G20RR024001 from the National Center for Research Resources, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, USA

    V H Rao, A Kandel, D Lynch, Z Pena, N Marwaha & L A Hansen

  2. Department of Pathology, Creighton University School of Medicine, Omaha, NE, USA

    C Deng

  3. Department of Preventive Health, Creighton University School of Medicine, Omaha, NE, USA

    P Watson

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Correspondence to L A Hansen.

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Dr Hansen's work has been funded by the NIH, the Nebraska Cancer and Smoking-Related Diseases Research Program and the Dobleman Institute for Head and Neck Cancer Research. The other authors declare no conflict of interest.

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Rao, V., Kandel, A., Lynch, D. et al. A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion. Oncogene 31, 2888–2898 (2012). https://doi.org/10.1038/onc.2011.460

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