title: Expression microarray meta-analysis identifies genes associated with Ras/MAPK and related pathways in progression of muscle-invasive bladder transition cell carcinoma.
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.
authors: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors: Jonathan A
authors: JA
authors: Ewald
authors: Tracy M
authors: TM
authors: Downs
authors: Jeremy P
authors: JP
authors: Cetnar
authors: William A
authors: WA
authors: Ricke
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D019295:Computational Biology; D024022:Fibrillar Collagens / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D046228:Microarray Analysis; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D024022:Fibrillar Collagens; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins
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