title: Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates pancreatic tumorigenesis.
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.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: S
authors.initials: S
authors.lastname: Jagadeeshan
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: Y R
authors.initials: YR
authors.lastname: Krishnamoorthy
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: M
authors.initials: M
authors.lastname: Singhal
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: A
authors.initials: A
authors.lastname: Subramanian
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: J
authors.initials: J
authors.lastname: Mavuluri
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: A
authors.initials: A
authors.lastname: Lakshmi
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: A
authors.initials: A
authors.lastname: Roshini
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Chennai, India.
authors.forename: G
authors.initials: G
authors.lastname: Baskar
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Chennai, India.
authors.forename: M
authors.initials: M
authors.lastname: Ravi
authors.affiliation: Department of Pathology, Sri Ramachandra University, Chennai, India.
authors.forename: L D
authors.initials: LD
authors.lastname: Joseph
authors.affiliation: Department of Plastic and Reconstructive Surgery, Government Medical College, Thiruvananthapuram, India.
authors.forename: K
authors.initials: K
authors.lastname: Sadasivan
authors.affiliation: Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India.
authors.forename: A
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India.
authors.forename: A S
authors.initials: AS
authors.lastname: Nair
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Chennai, India.
authors.forename: G
authors.initials: G
authors.lastname: Venkatraman
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: S K
authors.initials: SK
authors.lastname: Rayala
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005353:Fibronectins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051996:Transcription Factor RelA / Q000502:physiology; D014158:Transcription, Genetic; D054462:p21-Activated Kinases / Q000502:physiology*
chemical_list: D005353:Fibronectins; D051996:Transcription Factor RelA; D054462:p21-Activated Kinases