An Inactivating CYLD Mutation Promotes Skin Tumor Progression by Conferring Enhanced Proliferative, Survival and Angiogenic Properties to Epidermal Cancer Cells

Oncogene. 2010 Dec 16;29(50):6522-32. doi: 10.1038/onc.2010.378. Epub 2010 Sep 13.

Abstract

In this study, we demonstrate that the expression in tumorigenic epidermal cells of a catalytically inactive form of CYLD (CYLD(C/S)) that mimics the identified mutations of cyld in human tumors and competes with the endogenous CYLD results in enhanced cell proliferation and inhibition of apoptosis; it also stimulates cell migration and induces the expression of angiogenic factors, including vascular endothelial growth factor-A. Altogether, these characteristics indicate an increased oncogenicity of the tumorigenic epidermal CYLD(C/S) mutant cells in vitro. Moreover, we show the increase in malignancy of epidermal squamous cell carcinomas that express the CYLD(C/S) transgene in an in vivo xenograft model. Tumors carrying the mutated CYLD(C/S) exhibit a fast growth, are poorly differentiated and present a robust angiogenesis. CYLD(C/S) tumors are also characterized by their elevated proliferation rate and decreased apoptosis. In contrast with previous studies showing the development of benign tumors by mutations in the CYLD gene, here we provide evidence that the occurrence of mutations in the CYLD gene in tumorigenic epidermal cells (carrying previous mutations) increases the aggressiveness of carcinomas, mainly through enhancement of the expression of angiogenic factors, having therefore a key role in epidermal cancer malignancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation*
  • Cell Survival
  • Deubiquitinating Enzyme CYLD
  • Disease Progression
  • Humans
  • Mice
  • Mice, Nude
  • Mutation*
  • Neovascularization, Pathologic / genetics*
  • Skin Neoplasms / blood supply*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology*
  • Tumor Suppressor Proteins / genetics*
  • Vascular Endothelial Growth Factor A / analysis

Substances

  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD