VHL promotes immune response against renal cell carcinoma via NF-κB-dependent regulation of VCAM-1

J Cell Biol. 2017 Mar 6;216(3):835-847. doi: 10.1083/jcb.201608024. Epub 2017 Feb 24.

Abstract

Vascular cell adhesion molecule 1 (VCAM-1) is an adhesion molecule assigned to the activated endothelium mediating immune cells adhesion and extravasation. However, its expression in renal carcinomas inversely correlates with tumor malignancy. Our experiments in clear cell renal cell carcinoma (ccRCC) cell lines demonstrated that von Hippel Lindau (VHL) loss, hypoxia, or PHD (for prolyl hydroxylase domain-containing proteins) inactivation decreased VCAM-1 levels through a transcriptional mechanism that was independent of the hypoxia-inducible factor and dependent on the nuclear factor κB signaling pathway. Conversely, VHL expression leads to high VCAM-1 levels in ccRCC, which in turn leads to better outcomes, possibly by favoring antitumor immunity through VCAM-1 interaction with the α4β1 integrin expressed in immune cells. Remarkably, in ccRCC human samples with VHL nonmissense mutations, we observed a negative correlation between VCAM-1 levels and ccRCC stage, microvascular invasion, and symptom presentation, pointing out the clinical value of VCAM-1 levels as a marker of ccRCC progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / immunology
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / immunology*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / immunology
  • Integrin alpha4beta1 / genetics
  • Integrin alpha4beta1 / immunology
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / immunology*
  • Mutation / genetics
  • Mutation / immunology
  • NF-kappa B / genetics*
  • NF-kappa B / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Transcription, Genetic / genetics
  • Transcription, Genetic / immunology
  • Vascular Cell Adhesion Molecule-1 / genetics*
  • Vascular Cell Adhesion Molecule-1 / immunology
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / immunology
  • von Hippel-Lindau Disease / genetics
  • von Hippel-Lindau Disease / immunology*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Integrin alpha4beta1
  • NF-kappa B
  • Vascular Cell Adhesion Molecule-1
  • Von Hippel-Lindau Tumor Suppressor Protein