Similar to Rac Cdc and RhoA
Similar to Rac1, Cdc42, and RhoA, expression of Rnd3 is also increased under hypoxic conditions, involving Hif1α mediated transcriptional activity. Here, downregulation of Rnd3 abolishes hypoxia-induced cell migration via a mechanism involving the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4) (Feng et al., 2013), a GPCR that is often aberrantly expressed in malignant cells (Balkwill, 2004). Expression of both CXCR4 receptor and its ligand stromal cell derived factor-1 (SDF1) are under control by Hif1α mediated transcription (Burger & Kipps, 2006). Indeed, tumors with inactivating mutations in pVHL express simultaneously high levels of SDF1 and CXCR4 (Staller et al., 2003, Zagzag et al., 2005). Functionally, binding of SDF1 to CXCR4 induces expression of genes involved in cell invasion, and as such mediate metastatic behavior of cancer cells (Teicher & Fricker, 2010). Ultimately, this enables tumor cells to escape from hypoxic areas by migrating towards a gradient of SDF1. Indeed, silencing of either CXCR4 or Hif1α decreases migration of colorectal carcinoma cells (Romain et al., 2014). The mechanisms of Hif1α/CXCR4 interaction are still under investigation, but recent reports suggest the involvement of PDZ-RhoGEF-mediated activation of RhoA (Guo et al., 2016, Struckhoff et al., 2013). One of the best recognized target genes of Hif1α is vascular endothelial growth factor (VEGF), one of the major growth factors regulating angiogenesis and as such, AXL1717 synthesis to hypoxia. Expression of VEGF is essential in cancer progression by affecting both endothelial cells as well as being part of autocrine signaling cascades involved in regulating important characteristics of cancer cells, including EMT (Goel & Mercurio, 2013). Early studies in breast cancer have shown that overexpression of RhoC increased VEGF expression and secretion (van Golen et al., 2002, van Golen et al., 2000a, van Golen et al., 2000b). Similarly, expression of constitutively active RhoC increases expression of VEGF in breast carcinoma (Wu, Wu, Kumar-Sinha, Chinnaiyan, & Merajver, 2004). Of particular interest are findings that show that RhoC is crucial for the interaction between malignant cells and endothelial cells, a process which is required for transendothelial cell migration, underlying metastasis (Reymond et al., 2012, Reymond et al., 2015, Reymond et al., 2012). Activation of Hif1α is linked to EMT in cancer cells and as such downregulation of Hif1α suppresses cell migration and invasion (Krishnamachary et al., 2003, Sahlgren et al., 2008). Earlier we discussed the involvement of PGE2, Rho proteins and its effectors in dissociation of the adherens junctional complex and in activating β-catenin-dependent transcription. In this regard, studies on β-catenin transcriptional activity under hypoxic conditions are of particular interest. Expression of COX-2 is regulated by Hif1α through Hif1α binding to the hypoxia response elements (HRE) in the COX-2 promoter region, leading to increased PGE2 levels (Csiki et al., 2006, Kaidi et al., 2006). Silencing of Hif1α negatively affects stability and transcriptional activity of β-catenin and results in the restoration of β-catenin to E-cadherin at the adherens junctions (Santoyo-Ramos, Likhatcheva, Garcia-Zepeda, Castaneda-Patlan, & Robles-Flores, 2014). Moreover, silencing of β-catenin reversed the hypoxia-induced EMT features and attenuated invasion and metastasis (Liu et al., 2010), indicating that the interaction between β-catenin and Hif1α allows for the increased invasive capacity of carcinoma cells (Zhang et al., 2013). On the other hand, hypoxia inhibits β-catenin/TCF complex formation and thereby inhibits β-catenin transcriptional activity (Kaidi, Williams, & Paraskeva, 2007). It is believed that this is the consequence of Hif1α and TCF competing for direct binding of β-catenin. The interaction between Hif1α and β-catenin occurs at the promoter region of Hif1α target genes and as such, β-catenin can promote Hif1α-mediated gene transcription, promoting cellular adaptation to hypoxia. Conversely, β-catenin associating with Hif1α may override the normal proliferative effect of PGE2 on carcinoma cells, which is dependent on TCF-mediated gene transcription, and shifts towards Hif1α-mediated adaptation to hypoxia (Greenhough et al., 2009).