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MUC5AC interactions with integrin β4 enhances the migration of lung cancer cells through FAK signaling

Oncogene volume 35, pages 4112–4121 (2016)Cite this article

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Abstract

MUC5AC is a secretory mucin aberrantly expressed in various cancers. In lung cancer, MUC5AC is overexpressed in both primary and metastatic lesions; however, its functional role is not well understood. The present study was aimed at evaluating mechanistic role of MUC5AC on metastasis of lung cancer cells. Clinically, the overexpression of MUC5AC was observed in lung cancer patient tissues and was associated with poor survival. In addition, the overexpression of Muc5ac was also observed in genetically engineered mouse lung adenocarcinoma tissues (KrasG12D; Trp53R172H/+; AdCre) in comparison with normal lung tissues. Our functional studies showed that MUC5AC knockdown resulted in significantly decreased migration in two lung cancer cell lines (A549 and H1437) as compared with scramble cells. Expression of integrins (α5, β1, β3, β4 and β5) was decreased in MUC5AC knockdown cells. As both integrins and MUC5AC have a von Willebrand factor domain, we assessed for possible interaction of MUC5AC and integrins in lung cancer cells. MUC5AC strongly interacted only with integrin β4. The co-localization of MUC5AC and integrin β4 was observed both in A549 lung cancer cells as well as genetically engineered mouse adenocarcinoma tissues. Activated integrins recruit focal adhesion kinase (FAK) that mediates metastatic downstream signaling pathways. Phosphorylation of FAK (Y397) was decreased in MUC5AC knockdown cells. MUC5AC/integrin β4/FAK-mediated lung cancer cell migration was confirmed through experiments utilizing a phosphorylation (Y397)-specific FAK inhibitor. In conclusion, overexpression of MUC5AC is a poor prognostic marker in lung cancer. MUC5AC interacts with integrin β4 that mediates phosphorylation of FAK at Y397 leading to lung cancer cell migration.

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Acknowledgements

We acknowledge the valuable technical support from Mrs Kavita Mallya and Ms Lynette Smith. We also thank Janice A Tayor and James R Talaska, of the confocal laser scanning microscope core facility at UNMC, for their support. The work is partly supported by grants from the US Department of Veterans’ Affairs, UNMC Department of Internal Medicine Summer Undergraduate Research Program and Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727) and National Institutes of Health (P50 CA127297, U54 CA163120, RO1 CA183459, RO1 CA195586, K22 CA175260 and P20 GM103480).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    I Lakshmanan, S Rachagani, R Hauke, S R Krishn, P Seshacharyulu, S Karmakar, R K Nimmakayala, G Kaushik, M P Ponnusamy, S Kaur & S K Batra

  2. Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    S Paknikar & A K Ganti

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    S L Johansson

  4. Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center University of Nebraska Medical Center, Omaha, NE, USA

    S L Johansson, M P Ponnusamy & S K Batra

  5. Department of Medicine, Section of Hematology-Oncology, University of Chicago, Chicago, IL, USA

    G B Carey

  6. Department of Internal Medicine, VA Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE, USA

    A K Ganti

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  1. I Lakshmanan
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Lakshmanan, I., Rachagani, S., Hauke, R. et al. MUC5AC interactions with integrin β4 enhances the migration of lung cancer cells through FAK signaling. Oncogene 35, 4112–4121 (2016). https://doi.org/10.1038/onc.2015.478

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