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?-Catenin regulates proliferation and apoptosis in renal cell carcinoma via promoting ?-catenin nuclear localization and activating its downstream target genes.

ABSTRACT: ?-Catenin is a unique member of the catenin family and is proved to be overexpressed in diverse human cancer types. However, the clinical significance and underling mechanism of ?-catenin expression in renal cell carcinoma (RCC) remain elusive. Herein, we detected the protein expression of ?-catenin in 28 clinical specimens of paired renal cancer tissues and normal renal tissues by Western blot analysis. ?-Catenin expression in 58 cases of renal cell carcinoma was also examined by immunohistochemistry, and its association with clinicopathological factors was analyzed by statistical analysis. In vitro and in vivo assays were employed to further explore the biological role of ?-catenin in RCC. The results showed that ?-catenin was highly expressed in both clinical samples and cell lines of RCC. RCC patients with higher ?-catenin expression had a more advanced pTNM stage and tumor stage as well as lymph nodes metastasis than those with lower expression. By regulating the nuclear translocation of ?-catenin and ?-catenin-mediated oncogenic signals, ?-catenin promoted proliferation and inhibited apoptosis in RCC. In vivo assay indicated ?-catenin facilitated tumor growth in ACHN cell xenograft mouse model. Taken together, our study suggests that ?-catenin might be considered as a novel prognostic indicator and actionable target for gene therapy in renal cell carcinoma.

SUBMITTER: Ju L

PROVIDER: S-EPMC7064116 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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δ-Catenin regulates proliferation and apoptosis in renal cell carcinoma via promoting β-catenin nuclear localization and activating its downstream target genes.

Ju Lincheng L Shan Liping L Yin Bo B Song Yongsheng Y Song Yongsheng Y

Cancer medicine 20200128 6

δ-Catenin is a unique member of the catenin family and is proved to be overexpressed in diverse human cancer types. However, the clinical significance and underling mechanism of δ-catenin expression in renal cell carcinoma (RCC) remain elusive. Herein, we detected the protein expression of δ-catenin in 28 clinical specimens of paired renal cancer tissues and normal renal tissues by Western blot analysis. δ-Catenin expression in 58 cases of renal cell carcinoma was also examined by immunohistoche ...[more]

PMID: 31991069

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Project description:BACKGROUND:Aberrant Wnt/?-catenin signaling is associated with breast cancer even though genetic mutations in Wnt signaling components are rare. We have previously demonstrated that Rad6B, an ubiquitin conjugating enzyme, stabilizes ?-catenin via polyubiqutin modifications that render ?-catenin insensitive to proteasomal degradation. Rad6B is a transcriptional target of ?-catenin, creating a positive feedback loop between Rad6B expression and ?-catenin activation. METHODS:To isolate subpopulations expressing high or low Rad6B levels, we transfected MDA-MB-231 or WS-15 human breast cancer cells with ZsGreen fluorescent reporter vector in which the expression of ZsGreen was placed under the control of Rad6B promoter. ZsGreenhigh and ZsGreenlow subpopulations, reflective of high and low Rad6B promoter activity, respectively, were isolated by FACS. To determine the relevance of Wnt signaling in Rad6B-mediated ?-catenin stabilization/activation, the ZsGreenhigh cells were transfected with signaling-defective Wnt coreceptor LRP6?173. Rad6B expression and promoter activity were determined by RT-PCR, Western blot and Rad6B promoter-mediated luciferase assays. ?-catenin levels and transcriptional activity were determined by Western blot and TOP/FOP Flash reporter assays. Tumor formation and morphologies of ZsGreenlow, ZsGreenhigh, and ZsGreenhigh/LRP6?173 cells compared to unsorted vector controls were evaluated in nude mice. Expression of Wnt signaling related genes was profiled using the Wnt signaling pathway RT2 Profiler PCR arrays. RESULTS:ZsGreenhigh subpopulations showed high Rad6B expression and Rad6B promoter activity as compared to ZsGreenlow cells. ZsGreenhigh (high Rad6B expressors) also showed elevated ?-catenin levels and TOP/Flash activity. Inhibiting Wnt signaling in the high Rad6B expressors decreased ZsGreen fluorescence, Rad6B gene expression, ?-catenin levels and TOP/Flash activity. Tumors derived from high Rad6B expressors were predominantly composed of cells with epithelial mesenchymal transition (EMT) phenotype as compared to control tumors that were composed of both cuboidal and EMT-type cells. Tumors derived from low Rad6B expressors lacked EMT phenotype. Inhibition of LRP6 function in the high Rad6B expressors abrogated the EMT phenotype. Gene expression profiling showed upregulation of several Wnt signaling pathway regulators in high Rad6B expressors that were downregulated by interference of Wnt signaling with mutant LRP6 or by Rad6B silencing. CONCLUSIONS:These data reveal a functional link between the canonical Wnt pathway and Rad6B in ?-catenin activation and breast cancer progression.

Dataset Information

?-Catenin regulates proliferation and apoptosis in renal cell carcinoma via promoting ?-catenin nuclear localization and activating its downstream target genes.

Publications

δ-Catenin regulates proliferation and apoptosis in renal cell carcinoma via promoting β-catenin nuclear localization and activating its downstream target genes.

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