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

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