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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Renal Cancer | Research

Claudin-2 inhibits renal clear cell carcinoma progression by inhibiting YAP-activation

Authors: Balawant Kumar, Rizwan Ahmad, Giovanna A. Giannico, Roy Zent, Geoffrey A. Talmon, Raymond C. Harris, Peter E. Clark, Vinata Lokeshwar, Punita Dhawan, Amar B. Singh

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Claudin-2 expression is upregulated in multiple cancers and promotes cancer malignancy. Remarkably, the regulation of claudin-2 expression in kidney cell lines contrasts its reported regulation in other organs. However, claudin-2 role in renal clear cell carcinoma (RCC) remains unknown despite its predominant expression in the proximal tubular epithelium (PTE), the site of RCC origin.

Methods

Publicly available and independent patient databases were examined for claudin-2 association with RCC. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by Mass spectroscopy, immunoprecipitation and mutational studies, and functional evaluations.

Results

We show that the significant decrease in claudin-2 expression characterized PTE cells and Ex-vivo cultured mouse kidney subjected to dedifferentiation. Inhibition of claudin-2 was enough to induce mesenchymal plasticity and invasive mobility in these models. Further, a progressive loss of claudin-2 expression associated with the RCC progression and poor patient survival. Overexpression of claudin-2 in RCC-derived cancer cells inhibited tumorigenic abilities and xenograft tumor growth. These data supported a novel tumor-suppressive role of claudin-2 in RCC. Mechanistic insights further revealed that claudin-2 associates with YAP-protein and modulates its phosphorylation (S127) and nuclear expression. The tumor suppressive effects of claudin-2 expression were lost upon deletion of its PDZ-binding motif emphasizing the critical role of the PDZ-domain in claudin-2 interaction with YAP in regulating RCC malignancy.

Conclusions

Our results demonstrate a novel kidney specific tumor suppressive role for claudin-2 protein and further demonstrate that claudin-2 co-operates with the YAP signaling in regulating the RCC malignancy.

Available only for authorised users

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Title: Claudin-2 inhibits renal clear cell carcinoma progression by inhibiting YAP-activation
Authors: Balawant Kumar
Rizwan Ahmad
Giovanna A. Giannico
Roy Zent
Geoffrey A. Talmon
Raymond C. Harris
Peter E. Clark
Vinata Lokeshwar
Punita Dhawan
Amar B. Singh
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Renal Cancer
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01870-5

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Abstract

Background

Methods

Results

Conclusions

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