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  • Numerous studies have investigated the contribution


    Numerous studies have investigated the contribution of N-cadherin to metastasis and tumorigenesis. The overexpression of N-cadherin has been shown to enhance tumor invasion and motility in multiple cancer models [25,40,48]. Transforming growth factor beta 1 (TGFβ1) is a strong EMT inducer. In fact, TGFβ1 can drive cadherin switching, resulting in the loss of E-cadherin, an increased expression of N-cadherin, and an increase of cell motility. The importance of N-cadherin in TGFβ-induced cancer cell motility was recently illustrated by Kang et al., [49] who ablated N-cadherin expression via shRNA and found that TGFβ no longer increased cell motility. This highlights that the increase of N-cadherin as a result of cadherin switching is important for the enhanced migration of cancer BB94 that have undergone EMT. Moreover, N-cadherin has been shown to promote cell survival. For example, hepatocellular carcinoma cells expressing a dominant-negative form of N-cadherin are more susceptible to bile acid-induced apoptosis [50]. Additionally, melanoma cells can use N-cadherin-mediated adhesion to activate the AKT signaling pathway and deflect apoptosis [51]. Multiple groups have investigated the importance of N-cadherin in tumorigenesis through the development of transgenic mice. Knudsen et al. [52] drove N-cadherin expression under control of the mouse mammary tumor virus (MMTV) promoter and found that tumor growth and progression, regardless of the presence of the neu oncogene, was unaffected. In contrast, Hulit et al. [53] crossed the MMTV-N-cadherin mice with mice expressing polyoma virus middle-T antigen and found that forced N-cadherin expression increased metastasis. The effect of forced N-cadherin expression on pancreatic cancer progression was investigated in an orthotopic implantation xenograft model, which revealed that tumor cell overexpression of N-cadherin increased metastasis that was inhibited by peptides that antagonize N-cadherin [25]. Interestingly, N-cadherin-blocking peptides also reduced primary tumor growth in this model. In contrast, a recent study found that global deletion of N-cadherin led to a hyperproliferation and acceleration of pancreatic intraepithelial neoplasia (PanIN) during Kras-driven PanIN lesion progression [54]. This was accompanied by a decrease of E-cadherin and redistribution of β-catenin, suggesting that while N-cadherin can activate various growth factor signaling processes that contribute to tumor progression and increase cell migratory capability, it also has a tumor suppressing function, potentially by stabilizing E-cadherin and sequestering β-cadherin during early tumor development. These studies highlight that the contribution of N-cadherin to tumor progression is context-dependent. Another way that cadherin switching can affect cell behavior is by regulating Rho GTPases. E-cadherin-mediated cell-cell contacts rapidly activate Rac1 and Cdc42 and decrease RhoA activity [55,56]. Homophilic interactions of E-cadherin molecules results in the recruitment of Rac1 to the adhesion site, leading to its activation. The activation of Rac1 in this manner is dependent upon phosphatidylinositol 3-kinase (PI3K), as PI3K inhibition blocks E-cadherin-induced Rac1 activation, although it does not affect the localization of Rac1. During cadherin switching, the expression of N-cadherin or R-cadherin can also enhance the activity of Rac1 and Cdc42, leading to an increase of cell movement [57,58]. Of all the proteins within the cadherin-catenin complex, p120 catenin is most well-studied in the context of Rho GTPase activity. The p120 catenin binds to the juxtamembrane region of classical cadherins, including E-cadherin, N-cadherin, and P-cadherin [20]. This interaction is important for cadherin protein stability where it reduces cadherin turnover. In contrast, cytosolic p120 catenin that is not bound to cadherins inhibits RhoA activity [30]; p120 catenin can inhibit RhoA by direct interaction as a GDI, can activate Rho GEFs such as Vav2, and can interact with p190RhoGAP [35]. Therefore, the cadherin proteins are able to sequester p120 catenin from inhibiting RhoA activity, thus indirectly regulating Rho GTPase-signaling pathways. Since the binding affinity with p120 catenin is different between E-cadherin and N-cadherin, cadherin switching might have a differential effect on RhoA activity [59]. Interestingly, during EMT, a switch between p120 catenin isoforms also occurs with isoform 3 switching to isoform 1 due to alternative splicing, which is associated with enhanced cancer cell invasion [60].