Expression microarray meta-analysis identifies genes associated with Ras/MAPK and related pathways in progression of muscle-invasive bladder transition cell carcinoma

PLoS One. 2013;8(2):e55414. doi: 10.1371/journal.pone.0055414. Epub 2013 Feb 1.

Abstract

The effective detection and management of muscle-invasive bladder Transition Cell Carcinoma (TCC) continues to be an urgent clinical challenge. While some differences of gene expression and function in papillary (Ta), superficial (T1) and muscle-invasive (≥T2) bladder cancers have been investigated, the understanding of mechanisms involved in the progression of bladder tumors remains incomplete. Statistical methods of pathway-enrichment, cluster analysis and text-mining can extract and help interpret functional information about gene expression patterns in large sets of genomic data. The public availability of patient-derived expression microarray data allows open access and analysis of large amounts of clinical data. Using these resources, we investigated gene expression differences associated with tumor progression and muscle-invasive TCC. Gene expression was calculated relative to Ta tumors to assess progression-associated differences, revealing a network of genes related to Ras/MAPK and PI3K signaling pathways with increased expression. Further, we identified genes within this network that are similarly expressed in superficial Ta and T1 stages but altered in muscle-invasive T2 tumors, finding 7 genes (COL3A1, COL5A1, COL11A1, FN1, ErbB3, MAPK10 and CDC25C) whose expression patterns in muscle-invasive tumors are consistent in 5 to 7 independent outside microarray studies. Further, we found increased expression of the fibrillar collagen proteins COL3A1 and COL5A1 in muscle-invasive tumor samples and metastatic T24 cells. Our results suggest that increased expression of genes involved in mitogenic signaling may support the progression of muscle-invasive bladder tumors that generally lack activating mutations in these pathways, while expression changes of fibrillar collagens, fibronectin and specific signaling proteins are associated with muscle-invasive disease. These results identify potential biomarkers and targets for TCC treatments, and provide an integrated systems-level perspective of TCC pathobiology to inform future studies.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Blotting, Western
  • Carcinoma, Transitional Cell / genetics*
  • Carcinoma, Transitional Cell / pathology
  • Computational Biology
  • Fibrillar Collagens / metabolism
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • Immunohistochemistry
  • Microarray Analysis
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism*
  • Muscle, Skeletal / pathology*
  • Neoplasm Invasiveness / pathology
  • Signal Transduction / genetics*
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • ras Proteins / metabolism*

Substances

  • Fibrillar Collagens
  • Mitogen-Activated Protein Kinases
  • ras Proteins