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2012). formation (van Miltenburg et al. 2014). FAK inhibition by FAK siRNA-mediated knockdown or overexpressing the FAK CD can decrease cell proliferation and tumor growth in breast malignancy cells (Golubovskaya et al. 2009). Collectively, these studies suggest that FAK is critical in malignancy cell survival. Regulation of Malignancy Stem Cells Malignancy stem cells (CSCs) have the ability to self-renew and to differentiate into malignancy cells from a rare populace of undifferentiated tumorigenic cells (Patel and Chen 2012). CSCs were first isolated from leukemia (Bonnet and Dick 1997) and, later, from many solid tumors, including brain, breast, prostate and pancreas cancers (Al-Hajj et al. 2003; Li et al. 2007; Li et al. 2009; Patrawala et al. 2006; Singh et al. 2003). CSCs generally contain specific cell surface markers, such as CD133, CD44, CD90, and CD24 (Anido et al. 2010; Singh et al. 2003) in addition to expressing specific transcription factors (Liu et al. 2013). FAK deletion in a murine breast cancer model led to a decrease in the number of mammary CSCs and a decrease in their self-renewal potential; this ultimately inhibited tumor progression (Luo et al. 2009a). Recent studies have also indicated that FAK is usually involved in the expression of several stem cell factors. FAK maintains the expression of crucial transcription factors Slug (Snail family zinc finger 2) and Sox9, which were identified as important factors in maintaining mammary CSCs (Guo et al. 2012). In addition, NANOG, a key marker in stem cells, increases the level of FAK expression and activity in 293, SW480, and SW620 malignancy cells (Ho et al. 2012). NANOG directly binds to the FAK promoter triggering FAK expression, and studies show that downregulating NANOG expression by siRNA can inhibit malignancy cell growth, which can be reversed by FAK overexpression (Ho et al. 2012). These studies show that FAK expression may have an important role in the control of CSC function and activity. Epithelial-to-Mesenchymal Transition (EMT) EMT is usually a crucial process during embryogenesis, development, tissue remodeling and tumor progression. Over the past decade, numerous regulators have been identified as essential transcription factors in EMT, such as Snail, Slug, Twist, and Zeb (Chui 2013; Wang et al. 2013). EMT ultimately requires a decrease in epithelial markers (E-cadherin, -catenin, and -catenin), an increase in mesenchymal markers (vimentin, fibronectin, and N-cadherin) and the secretion of matrix metalloproteinases (MMPs). These changes in cell phenotype and genetic modulation promote a transition from benign tumor to invasive carcinoma. Recent studies have identified evidence of FAK involvement in the EMT process. FAK has a functional role in TGF–mediated EMT by Src-dependent activation in hepatocytes Rabbit Polyclonal to SEPT7 (Cicchini et al. 2008). These studies revealed that FAK signaling is required for the transcriptional regulation of several mesenchymal markers and for the delocalization of E-cadherin. Additionally, a FAK inhibitor (1,2,4,5-benzenentetramine, 4HCl) repressed TGF–induced EMT in human squamous cell carcinoma (Saito et al. 2013). FAK signaling was NVS-PAK1-1 required for Src-regulated E-cadherin expression in colon cancer cells, and inhibition of FAK activity reduced Src-mediated cell invasion (Avizienyte et al. 2002; Hauck et al. 2002a). More direct evidence of FAK involvement in EMT has been provided from a recent study of FAK-/- embryonic cells. FAK re-expression rescued the mesenchymal characteristics of FAK-/- embryonic cells to generate committed mouse embryonic fibroblasts via Snail1 gene expression and Snail1 NVS-PAK1-1 protein stabilization (Li et al. 2011). Taken together, even though direct role of FAK is usually yet to be unveiled in EMT, the correlation between FAK and EMT may offer an important target in malignancy metastasis and malignancy therapeutics. Invasion and Metastasis FAK overexpression is also associated with the enhanced invasion and metastatic characteristics of EMT (Cance et al. 2000a). Integrin 1 and FAK signaling directly regulate the proliferation and invasion of metastatic cells in the lung (Shibue and Weinberg 2009). FAK phosphorylation is usually important in regulating E-cadherin expression by activating Src signaling pathways in colon cancers and, before small molecule FAK inhibitors were available, overexpression of the FAK CD was useful in inhibiting malignancy cell invasion and metastasis (Hauck et al. 2002b). Furthermore, FAK promotes cellular membrane expression of MT1-MMP, a matrix metalloproteinase, which serves to degrade the ECM (Wu et al. 2005). A recent study from Schlaepfers group highlighted the importance of FAK in the tumor environment. FAK plays an important role in mediating VEGF (vascular endothelial growth factor)-induced vascular permeability NVS-PAK1-1 by directly phosphorylating -catenin at Y142 (Chen et al. 2012). In addition,.