Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Oncogene. 2012 Mar 22;31(12):1493-503. doi: 10.1038/onc.2011.336. Epub 2011 Aug 8.

Abstract

Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscle-invasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / genetics*
  • Cell Proliferation
  • Cell Shape / drug effects
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Phosphorylation
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Transcriptional Activation
  • Up-Regulation
  • Urinary Bladder Neoplasms / genetics*

Substances

  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • fos-related antigen 1
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase