title: S100A4 promotes pancreatic cancer progression through a dual signaling pathway mediated by Src and focal adhesion kinase.
abstract: S100A4 expression is associated with poor clinical outcomes of patients with pancreatic cancer. The effects of loss or gain of S100A4 were examined in pancreatic cancer cell lines. S100A4 downregulation remarkably reduces cell migration and invasion, inhibits proliferation, and induces apoptosis in pancreatic tumor cells. S100A4 downregulation results in significant cell growth inhibition and apoptosis in response to TGF-β1, supporting a non-canonical role of S100A4 in pancreatic cancer. The role of S100A4 in tumor progression was studied by using an orthotopic human pancreatic cancer xenograft mouse model. Tumor mass is remarkably decreased in animals injected with S100A4-deficient pancreatic tumor cells. P27(Kip1) expression and cleaved caspase-3 are increased, while cyclin E expression is decreased, in S100A4-deficient pancreatic tumors in vivo. S100A4-deficient tumors have lower expression of vascular endothelial growth factor, suggesting reduced angiogenesis. Biochemical assays revealed that S100A4 activates Src and focal adhesion kinase (FAK) signaling events, and inhibition of both kinases is required to maximally block the tumorigenic potential of pancreatic cancer cells. These findings support that S100A4 plays an important role in pancreatic cancer progression in vivo and S100A4 promotes tumorigenic phenotypes of pancreatic cancer cells through the Src-FAK mediated dual signaling pathway.
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Pulin
authors: P
authors: Che
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Youfeng
authors: Y
authors: Yang
authors: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Xiaosi
authors: X
authors: Han
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Meng
authors: M
authors: Hu
authors: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Jeffery C
authors: JC
authors: Sellers
authors: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Angelina I
authors: AI
authors: Londono-Joshi
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Guo-Qiang
authors: GQ
authors: Cai
authors: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Donald J
authors: DJ
authors: Buchsbaum
authors: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: John D
authors: JD
authors: Christein
authors: Institute of Edible Fungi, Shanghai, China.
authors: Qinjiu
authors: Q
authors: Tang
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Dongquan
authors: D
authors: Chen
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Qianjun
authors: Q
authors: Li
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: William E
authors: WE
authors: Grizzle
authors: Center of Therapeutic Research for Hepatocellular Carcinoma, 302 hospital, Beijing, China.
authors: Yin Ying
authors: YY
authors: Lu
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Qiang
authors: Q
authors: Ding
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D019927:Cyclin E; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D053148:Caspase 3