Tumor Type-Dependent Function of the Par3 Polarity Protein in Skin Tumorigenesis

Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
Cancer cell (Impact Factor: 23.52). 09/2012; 22(3):389-403. DOI: 10.1016/j.ccr.2012.08.004
Source: PubMed


Cell polarization is crucial during development and tissue homeostasis and is regulated by conserved proteins of the Scribble, Crumbs, and Par complexes. In mouse skin tumorigenesis, Par3 deficiency results in reduced papilloma formation and growth. Par3 mediates its tumor-promoting activity through regulation of growth and survival, since Par3 deletion increases apoptosis and reduces growth in vivo and in vitro. In contrast, Par3-deficient mice are predisposed to formation of keratoacanthomas, cutaneous tumors thought to originate from different cellular origin and frequently observed in humans. Par3 expression is reduced in both mouse and human keratoacanthomas, indicating tumor-suppressive properties of Par3. Our results identify a dual function of Par3 in skin cancer, with both pro-oncogenic and tumor-suppressive activity depending on the tumor type.

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    • "aPKC functions to establish apical-basal polarity by specifying apical membrane identity and suppressing basolateral identity. This polarized architecture permits the assembly of signaling networks that appropriately interpret the cellular environment, and disrupted aPKC polarity can affect key signaling mediators involved in tumor growth and invasion, including Ras, NF-κB, Stat3, ERK1/2, and Rac1 (Sanz et al., 1999; Justilien and Fields, 2009; Iden et al., 2012; McCaffrey et al., 2012; Atwood et al., 2013; Halaoui and McCaffrey, 2014; Paul et al., 2014). Epithelial cells exhibit contact-inhibited growth, which depends on cell density constraints, rather than cell–cell contact (Puliafito et al., 2012; Eisenhoffer and Rosenblatt, 2013). "
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    ABSTRACT: Epithelial cells are major sites of malignant transformation. Atypical Protein Kinase C (aPKC) isoforms are overexpressed and activated in many cancer types. Using normal, highly polarized epithelial cells (MDCK and NMuMG), we report that aPKC gain-of-function overcomes contact inhibited growth and is sufficient for a transformed epithelial phenotype. In 2D cultures, aPKC induced cells to grow as stratified epithelia, whereas cells grew as solid spheres of non-polarized cells in 3D culture. aPKC associated with Mst1/2, which uncoupled Mst1/2 from Lats1/2 and promoted nuclear accumulation of Yap1. Importantly, Yap1 was necessary for aPKC-mediated overgrowth, but did not restore cell polarity defects, indicating that the two are separable events. In MDCK cells Yap1 was sequestered to cell-cell junctions by Amot, and aPKC overexpression resulted in loss of Amot expression and a spindle-like cell phenotype. Re-expression of Amot was sufficient to restore an epithelial cobblestone appearance, Yap1 localization, and growth control. In contrast, the effect of aPKC on Hippo/Yap signaling and overgrowth in NMuMG cells was independent of Amot. Finally, increased expression of aPKC in human cancers strongly correlated with increased nuclear accumulation of Yap1, indicating that the effect of aPKC on transformed growth by deregulating Hippo/Yap1 signaling may be clinically relevant. © 2015 by The American Society for Cell Biology.
    Preview · Article · Aug 2015 · Molecular biology of the cell
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    • "It is also believed that PAR proteins may be involved in multiple aspects of oncogenesis because a relationship exists between polarity dysfunction and cancer progression [14] [15] [16]. Defective or overexpressed PAR-3 proteins have been described in other cancers related to tumor development or metastases formation, including breast cancer [17] [18], hepatocellular carcinoma [19], or skin tumors [20]. In ccRCC, along with lower survival rates, we recently showed that the migration of tumor cells might be promoted by the overexpression of PAR-3 and that the cytoskeleton organization was significantly altered [13]. "
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    ABSTRACT: Clear cell renal cell carcinomas (ccRCC) represent 70% of renal cancers and several clinical and histolopathological factors are implicated in its prognosis. We recently demonstrated that the overexpression of PAR-3 protein encoded by the PARD3 gene could be implicated in renal oncogenesis. The object of this work was to study the association of intratumoral PAR-3 expression with known prognostic parameters and clinical outcome. In this aim, PAR-3 expression was assessed by immunohistochemistry in ccRCC tumors of 101 patients from 2003 to 2005. The immunostaining of PAR-3 was scored either as membranous (mPAR-3) or as both membranous and cytoplasmic (cPAR-3). Cytoplasmic PAR-3 was significantly associated with worse histopathological and clinical prognostic factors: Fuhrman grades 3 and 4, tumor necrosis, sarcomatoid component, adrenal invasion, renal and hilar fat invasion, eosinophilic component, a non-inactivated VHL gene, higher tumor grade, lymph node involvement, metastasis and worse clinical Eastern Cooperative Oncology Group (ECOG) and S classification scores. After multivariate analysis, two parameters were independently associated with cPAR-3: necrosis and eosinophilic components. In addition, cPAR-3 patients had shorter overall and progression free survivals independently from strong prognostic validated factors like metastases. A cytoplasmic expression of PAR-3 is therefore implicated in worse clinical and pathological cancer features in ccRCC and could be useful to identify patients with high risk tumors.
    Full-text · Article · Aug 2014 · Human pathology
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    • "For instance, treatment of prostate cancer cells with aurothiomalate was shown to disrupt the PKCι/Par6 complex, leading to caspase-3 activation and apoptosis [34]. Similarly, radiation-induced injury was shown to promote apoptosis via disruption of the Cdc42/Par6/atypical protein kinase C Par polarity complex that localizes to the TJ [35], and Par3 knockout and consequent withdrawal from the Par complex promoted apoptosis in keratinocytes [36]. Taken together, these and our observations suggest that perturbations of the Par complex and the TJ leads to apoptosis. "
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    ABSTRACT: We previously observed that the TGFbeta-Par6 pathway mediates loss of polarity and apoptosis in NMuMG cells. Here we investigate the contribution of Par6 versus TGFbeta receptor I activation to TGFbeta-induced apoptosis in association with changes in apico-basal polarity. We focus on the effect of Par6 activation on alpha6beta4 integrin expression and localization, and Nuclear Factor-kappaB (p65/RelA) activation, previously shown to mediate polarity-dependent cell survival. Using immunoblotting and/or immunofluorescence we investigated the effect of TGFbeta1 on apoptosis, alpha6, beta4 and beta1 integrin expression/localization, and p65/RelA phosphorylation/localization in monolayer and three-dimensional (3D) cultures of NMuMG cells with an overactive or inactive Par6 pathway. Results were quantified by band densitometry or as percent of 3D structures displaying a phenotype. Differences among means were compared by two-way ANOVA. Blocking Par6 activation inhibits TGFbeta-induced apoptosis. Par6 overactivation enhances TGFbeta-induced apoptosis, notably after 6-day exposure to TGFbeta (p < 0.001), a time when parental NMuMG cells no longer respond to TGFbeta apoptotic stimuli. 48-hour TGFbeta treatment reduced beta4 integrin levels in NMuMG monolayers and significantly reduced the basal localization of alpha6 (p < 0.001) and beta4 (p < 0.001) integrin in NMuMG 3D structures, which was dependent on both Par6 and TGFbeta receptor I activation and paralleled apoptotic response. After 6-day exposure to TGFbeta, Par6-dependent changes to beta4 integrin were no longer apparent, but there was reduced phosphorylation of p65/RelA (p < 0.001) only in Par6 overexpressing cells. Differences in p65/RelA localization were not observed among the different cell lines after 48-hour TGFbeta exposure. Par6 and TGFbeta receptor I activation are both necessary for TGFbeta-induced apoptosis in NMuMG cells. Importantly, Par6 overexpression enhances the sensitivity of NMuMG to TGFbeta-induced apoptosis, notably upon prolonged exposure to this growth factor, when NMuMG parental cells are usually apoptosis-resistant. Thus, endogenous Par6 level might be important in determining whether TGFbeta will function as either a pro-apoptotic or pro-survival factor in breast cancer, and potentially aid in predicting patient's prognosis and therapy response.
    Full-text · Article · Mar 2014 · Cancer Cell International
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