The complex roles of Wnt antagonists in RCC

Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, 4150 Clement Street, CA 94121, USA.
Nature Reviews Urology (Impact Factor: 4.84). 12/2011; 8(12):690-9. DOI: 10.1038/nrurol.2011.146
Source: PubMed


Renal cell carcinoma (RCC) is the most lethal of all the genitourinary cancers, as it is generally refractory to current treatment regimens, including chemotherapy and radiation therapy. Targeted therapies against critical signaling pathways associated with RCC pathogenesis, such as vascular endothelial growth factor, von Hippel-Lindau tumor suppressor and mammalian target of rapamycin, have shown limited efficacy so far. Thus, Wnt signaling, which is known to be intricately involved in the pathogenesis of RCC, has attracted much interest. Several Wnt signaling components have been examined in RCC, and, while studies suggest that Wnt signaling is constitutively active in RCC, the molecular mechanisms differ considerably from other human carcinomas. Increasing evidence indicates that secreted Wnt antagonists have important roles in RCC pathogenesis. Considering these vital roles, it has been postulated--and supported by experimental evidence--that the functional loss of Wnt antagonists, for example by promoter hypermethylation, can contribute to constitutive activation of the Wnt pathway, resulting in carcinogenesis through dysregulation of cell proliferation and differentiation. However, subsequent functional studies of these Wnt antagonists have demonstrated the inherent complexities underlying their role in RCC pathogenesis.

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    • "Several β-catenin signaling components have been examined in RCC recently, and β-catenin signaling may be constitutively active in RCC [13, 14]. Aberrant activation of β-catenin signaling is involved in RCC carcinogenesis and progression and in the overexpression or overactivation of β-catenin [13, 14] and oncogenic WNT10A ligand [15] as well as genetic or epigenetic dysregulation of WNT antagonists [16, 17]. β-Catenin overexpression in RCC was associated with increased incidence and poor prognosis [16, 18–20]. "
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    ABSTRACT: Dysregulated β -catenin signaling is intricately involved in renal cell carcinoma (RCC) carcinogenesis and progression. Determining potential β -catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for β -catenin signaling inhibitors involved in silico inquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell lines in vitro and 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound of Anisomeles indica, inhibited β -catenin signaling and reduced RCC cell viability, survival, migration/invasion, and in vitro cell or in vivo mouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylated β -catenin (S552) that inhibited β -catenin nuclear translocation. Moreover, ovatodiolide decreased β -catenin stability and impaired the association of β -catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potent β -catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.
    Evidence-based Complementary and Alternative Medicine 05/2013; 2013(12):161628. DOI:10.1155/2013/161628 · 1.88 Impact Factor
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    ABSTRACT: Several genes play essential roles in human development and alteration of their expression or regulation leads to various pathologies. This review examines the literature on the expression and the roles of neurogenic locus notch homolog protein (NOTCH), sonic Hedgehog (SHH) and wingless-type (WNT) pathways, as well as the nephrogenic transcription factors Wilms' tumor 1 (WT1), paired box 2 (PAX2) and homeobox protein lim-1 (LIM1) in clear cell renal cell carcinoma. Besides being re-expressed in human tumors, the inhibition of these factors has strong antitumor activity both in vitro and in vivo. Interestingly, these pathways are also part of the molecular network involved in the development of organs including nephrogenesis. The identification of developmental pathways involved in clear cell renal cell carcinoma growth places an additional piece into the molecular puzzle of cancer mechanisms. Moreover, the evaluation of these molecules could pave the way to innovative and safe therapies for this refractory disease. Valuable prognostic markers might also be identified through these studies. Finally, the proof of concept in other types of cancer is reviewed.
    Anticancer research 09/2012; 32(9):3609-17. · 1.83 Impact Factor
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    ABSTRACT: Renal cell carcinoma (RCC) is a malignancy with poor prognosis. WNT/β-catenin signaling dysregulation, especially β-catenin overactivation and WNT antagonist silencing, is associated with RCC carcinogenesis and progression. However, the role of WNT ligands in RCC has not yet been determined. We screened 19 WNT ligands from normal kidney and RCC cell lines and tissues and found that WNT10A was significantly increased in RCC cell lines and tissues as compared to that in normal controls. The clinical significance of increase in WNT10A was evaluated by performing an immunohistochemical association study in a 19-year follow-up cohort comprising 284 RCC and 267 benign renal disease (BRD) patients. The results of this study showed that WNT10A was dramatically upregulated in RCC tissues as compared to that in BRD tissues. This result suggests that WNT10A, nuclear β-catenin, and nuclear cyclin D1 act as independent risk factors for RCC carcinogenesis and progression, with accumulative risk effects. Molecular validation of cell line models with gain- or loss-of-function designs showed that forced WNT10A expression induced RCC cell proliferation and aggressiveness, including higher chemoresistance, cell migration, invasiveness, and cell transformation, due to the activation of β-catenin-dependent signaling. Conversely, WNT10A siRNA knockdown decreased cell proliferation and aggressiveness of RCC cells. In conclusion, we showed that WNT10A acts as an autocrine oncogene both in RCC carcinogenesis and progression by activating WNT/β-catenin signaling.
    PLoS ONE 10/2012; 7(10):e47649. DOI:10.1371/journal.pone.0047649 · 3.23 Impact Factor
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