S100A4 promotes pancreatic cancer progression through a dual signaling pathway mediated by Src and focal adhesion kinase

• Published in: Scientific reports 2015-02, Vol.5 (1), p.8453-8453, Article 8453
• Main Authors: Che, Pulin, Yang, Youfeng, Han, Xiaosi, Hu, Meng, Sellers, Jeffery C., Londono-Joshi, Angelina I., Cai, Guo-Qiang, Buchsbaum, Donald J., Christein, John D., Tang, Qinjiu, Chen, Dongquan, Li, Qianjun, Grizzle, William E., Lu, Yin Ying, Ding, Qiang
• Format: Article
• Language: English
• Subjects: 13/89; 631/67/1504/1713; 631/80/86/2366; 64/60; 96/63; Adhesion; Angiogenesis; Animals; Apoptosis; Caspase; Caspase 3 - metabolism; Caspase-3; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cyclin E; Cyclin E - metabolism; Cyclin-dependent kinase inhibitor p27; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Down-Regulation; Female; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Humanities and Social Sciences; Humans; Mice; Mice, SCID; multidisciplinary; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; S100 Calcium-Binding Protein A4; S100 Proteins - antagonists & inhibitors; S100 Proteins - genetics; S100 Proteins - metabolism; S100A4 protein; Science; Signal Transduction; Src protein; src-Family Kinases - metabolism; Transforming Growth Factor beta1 - pharmacology; Transforming growth factor-b1; Transplantation, Heterologous; Tumor cell lines; Tumor cells; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep08453

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.