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

Balawant Kumar1, Rizwan Ahmad1, Giovanna A Giannico2

  • 1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA.

Journal of Experimental & Clinical Cancer Research : CR
|February 24, 2021
PubMed
Abstract

Insights

Claudin-2 exhibits a novel tumor-suppressive role in kidney cancer, contrasting its role in other cancers. Its interaction with YAP signaling is key to regulating renal clear cell carcinoma (RCC) malignancy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Kidney Disease Research

Background:

  • Claudin-2 is upregulated in many cancers, promoting malignancy.
  • Its role in kidney cancer is unknown, despite expression in proximal tubular epithelium (PTE), the origin of renal clear cell carcinoma (RCC).

Purpose of the Study:

  • To investigate the role of claudin-2 in renal clear cell carcinoma (RCC).
  • To elucidate the mechanism of claudin-2 action in kidney cancer.

Main Methods:

  • Analysis of patient databases for claudin-2 association with RCC.
  • In vitro and in vivo gain/loss of function assays.
  • Mass spectrometry, immunoprecipitation, mutational studies, and functional evaluations to determine mechanisms.

Main Results:

  • Decreased claudin-2 expression in PTE cells and dedifferentiated kidneys induced mesenchymal plasticity and invasive mobility.
  • Loss of claudin-2 correlated with RCC progression and poor survival.
  • Claudin-2 overexpression inhibited RCC cell tumorigenicity and xenograft growth, indicating a tumor-suppressive role.
  • Claudin-2 interacts with YAP, modulating its phosphorylation and nuclear expression, with the PDZ-binding motif being critical.

Conclusions:

  • Claudin-2 has a novel, kidney-specific tumor-suppressive role in RCC.
  • Claudin-2 cooperates with YAP signaling to regulate RCC malignancy.
Keywords:
De-differentiationHippo/yap signalingProliferationRenal Cancer

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