Podocalyxin EBP50 Ezrin Molecular Complex Enhances the Metastatic Potential of Renal Cell Carcinoma Through Recruiting Rac1 Guanine Nucleotide Exchange Factor ARHGEF7

Am J Pathol. 2010 Jun;176(6):3050-61. doi: 10.2353/ajpath.2010.090539. Epub 2010 Apr 15.

Abstract

Podocalyxin was initially identified in glomerular podocytes to critically maintain the structural and functional integrity of the glomerular ultrafiltrative apparatus. Lately, it has emerged as a malignant marker in tumors arising from a variety of tissue origins. By immunohistochemistry, we identified that 9.6% of renal cell carcinoma patients overexpress this protein. This subset of patients had significantly shorter disease-specific and overall survivals, and, importantly, we established podocalyxin overexpression as an independent prognostic factor for latent distant metastasis with multivariate analysis. Podocalyxin down-regulation by small interfering RNA led to defective migration in model renal tubular cells, which was corrected by re-expression of podocalyxin. The activity of the small GTPase Rac1, a well-characterized modulator of cell migration, was diminished by podocalyxin knock-down. Conversely, podocalyxin overexpression in human embryonic kidney cells up-regulated Rac1 activity, which depended on a complex formed by podocalyxin, ERM-binding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. Therefore, podocalyxin can serve as a biomarker to identify renal cell carcinoma patients with higher metastatic potential for more aggressive intervention at earlier clinical stages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology*
  • Cell Adhesion / physiology
  • Cell Line
  • Cell Movement / physiology
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Dogs
  • Enzyme Activation
  • Female
  • Gene Knockdown Techniques
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Multiprotein Complexes / metabolism*
  • Neoplasm Metastasis
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Rho Guanine Nucleotide Exchange Factors
  • Sialoglycoproteins / genetics
  • Sialoglycoproteins / metabolism*
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism*
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Cytoskeletal Proteins
  • Guanine Nucleotide Exchange Factors
  • Multiprotein Complexes
  • Phosphoproteins
  • Rho Guanine Nucleotide Exchange Factors
  • Sialoglycoproteins
  • Sodium-Hydrogen Exchangers
  • ezrin
  • podocalyxin
  • sodium-hydrogen exchanger regulatory factor
  • rac1 GTP-Binding Protein