Planar Polarity Factors as Potential Tumor Suppressors in the Urogenital Tract

Abstract

Planar Polarity Factors as Potential Tumor Suppressors in the Urogenital Tractby preventing their nuclear entry and induction of the cyclin E and anti-apoptotic proteins. In the absence of a Hippo signal, YAP and TAZ translocate to the nucleus and form transcriptional complexes with a number of factors, including beta-catenin, to promote cell division, survival, and migratory and invasive cell properties.Loss of FAT function contributes to many types of tumors, including the oral, breast, lung, pancreatic and gastric cancers, melanomas and hepatocellular carcinomas [7]. High levels of YAP1 protein correlate with cancer progression, and poor prognosis for the bladder, prostate, ovarian and uterine cancer patients [8][9][10][11][12]. In turn, irradiation induced apoptosis of prostate cancer cells has been linked to a decrease in the levels of the YAP1 protein and a consequent raise in the BAX cell death factor [12]. Both YAP and TAZ proteins have been implicated in cancer cell migration and metastasis [8,13,14]. The known antagonists of the Hippo pathway include the ciliaassociated protein NPHP4 [15] and the integrin-associated kinase, which mediate inhibition of Lats kinases upstream of the YAP/TAZ phosphorylation. The Lats 1/2 expression levels are downregulated in many advanced and metastatic cancers, including in prostate cancer, and this effect has been linked to cancer cell resistance to the attachment-dependent apoptosis [16].The core PCP pathway can be activated by most Wnt ligands, but has a preference for Wnt5a, Wnt9 and Wnt11, which have been designated as "non-canonical" Wnts. Although the Ft/Ds system is considered as the long distance PCP component, the core PCP pathway also has long distance capabilities, enabled by the diffusion of the Wnt ligands [17]. Formation of the Wnt/Fzd complexes is the first step in both the core PCP and Wnt/beta-catenin pathways. Thus, the former is often referred to as the "non-canonical Wnt" signaling. Assembly of the Fzd and Vangl receptor complexes on the apical cell surface appears to favor the PCP pathway [18]. In contrast to the canonical Wnt signaling, the core PCP pathway does not affect nuclear localization of beta-catenin. Furthermore, the core PCP signaling routinely antagonizes the canonical Wnt pathway, first, by recruiting Dvl to the membrane Vangl2 complexes, and also by sequestering other shared components (Wnts, Fzd and Frodo) and promoting the degradation of beta-catenin [19]. The canonical Wnt/beta-catenin signaling is often upregulated in cancers. Therefore, part of the PCP tumor suppressor role is likely exercised simply by suppressing the canonical Wnt targets, while another part is associated with its role in the maintenance of tissue polarity and cohesion.