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Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates pancreatic tumorigenesis

Oncogene volume 34, pages 455–464 (2015)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the eighth largest cause of cancer-related mortality across the world, with a median 5-year survival rate of less than 3.5%. This is partly because the molecules and the molecular mechanisms that contribute to PDAC are not well understood. Our goal is to understand the role of p21-activated kinase 1 (Pak1) signaling axis in the progression of PDAC. Pak1, a serine/threonine kinase, is a well-known regulator of cytoskeletal remodeling, cell motility, cell proliferation and cell survival. Recent reports suggest that Pak1 by itself can have an oncogenic role in a wide variety of cancers. In this study, we analyzed the expression of Pak1 in human pancreatic cancer tissues and found that Pak1 levels are significantly upregulated in PDAC samples as compared with adjacent normals. Further, to study the functional role of Pak1 in pancreatic cancer model systems, we developed stable overexpression and lentiviral short hairpin RNA-mediated knockdown (KD) clones of Pak1 and studied the changes in transforming properties of the cells. We also observed that Pak1 KD clones failed to form tumors in nude mice. By adopting a quantitative PCR array-based approach, we identified fibronectin, a component of the extracellular matrix and a mesenchymal marker, as a transcriptional target of Pak1 signaling. The underlying molecular mechanism of Pak1-mediated transformation includes its nuclear import and recruitment to the fibronectin promoter via interaction with nuclear factor-κB (NF-κB)–p65 complex. To our knowledge, this is the first study illustrating Pak1–NF-κB–p65-mediated fibronectin regulation as a potent tumor-promoting mechanism in KRAS intact model.

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Acknowledgements

We thank Silpa for help in mutagenesis and cloning and Swarnalatha for help with Pak1 lentiviral clones. Thanks to Sekar Sathiya, Rohan Prasad, Hemadev and the entire team of the Centre for Toxicology and Developmental Research (CEFT), Sri Ramachandra University, Chennai, for help with animal experiments. We thank the Department of Biotechnology (DBT), Government of India for the financial support to SKR (grant no.: BT/PR13559/Med/30/283/2010) and Indian Institute of Technology Madras (IITM) for all other facilities.

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Author notes

  1. S Jagadeeshan, Y R Krishnamoorthy, M Singhal and A Subramanian: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India

    S Jagadeeshan, Y R Krishnamoorthy, M Singhal, A Subramanian, J Mavuluri, A Lakshmi, A Roshini & S K Rayala

  2. Department of Human Genetics, Sri Ramachandra University, Chennai, India

    G Baskar, M Ravi & G Venkatraman

  3. Department of Pathology, Sri Ramachandra University, Chennai, India

    L D Joseph

  4. Department of Plastic and Reconstructive Surgery, Government Medical College, Thiruvananthapuram, India

    K Sadasivan

  5. Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India

    A Krishnan & A S Nair

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  1. S Jagadeeshan
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Correspondence to A S Nair, G Venkatraman or S K Rayala.

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Jagadeeshan, S., Krishnamoorthy, Y., Singhal, M. et al. Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates pancreatic tumorigenesis. Oncogene 34, 455–464 (2015). https://doi.org/10.1038/onc.2013.576

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  • DOI: https://doi.org/10.1038/onc.2013.576

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