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The Arkadia-ESRP2 axis suppresses tumor progression: analyses in clear-cell renal cell carcinoma

A Mizutani1,2, D Koinuma1, H Seimiya2

  • 1Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Oncogene
|November 3, 2015
PubMed

Insights

The Arkadia-ESRP2 axis suppresses clear-cell renal cell carcinoma (ccRCC) tumor growth. Lower Arkadia expression correlates with advanced ccRCC stages and poor patient outcomes, revealing a novel tumor-suppressive role.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Tumor-specific alternative splicing contributes to cancer progression, including clear-cell renal cell carcinoma (ccRCC).
  • Epithelial splicing regulatory protein 2 (ESRP2) is a key regulator of alternative splicing in epithelial cells and is expressed in ccRCC.
  • ESRP2 mRNA levels do not correlate with ccRCC patient survival, but some ESRP-target exon expression is linked to good prognosis.

Purpose of the Study:

  • To investigate the role of the epithelial splicing regulatory protein 2 (ESRP2) and its interaction with Arkadia (RNF111) in clear-cell renal cell carcinoma (ccRCC).
  • To elucidate the functional consequences of the Arkadia-ESRP2 axis on ccRCC tumor growth and patient prognosis.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) ccRCC RNA sequencing data.
  • Investigation of physical interaction and functional modulation between Arkadia and ESRP2.
  • Correlation analysis of gene expression with patient survival, tumor stage, and prognosis.

Main Results:

  • ESRP2 is expressed in ccRCC, and its target exon expression correlates with good prognosis and Arkadia expression.
  • Arkadia physically interacts with ESRP2, inducing polyubiquitination and modulating its splicing activity.
  • Coordinated suppression of ccRCC tumor growth by Arkadia and ESRP2 was observed.
  • Lower Arkadia expression is associated with advanced tumor stages and poorer outcomes in ccRCC patients.

Conclusions:

  • The Arkadia-ESRP2 axis plays a novel tumor-suppressive role in ccRCC.
  • Arkadia and ESRP2 function together to inhibit ccRCC tumor progression.
  • Arkadia expression level is a potential prognostic biomarker for ccRCC.

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