Original Article Cross-species comparison of orthologous gene expression in human bladder cancer and carcinogen-induced rodent models
Yan Lu, Pengyuan Liu, Weidong Wen, Clinton J Grubbs, Reid R Townsend, James P. Malone, Ronald A Lubet, and Ming You
Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Departments of Surgery, Genetics, and Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Chemoprevention Agent Development Research Group, National Cancer Institute, Rockville, MD 20892, USA; Department of Physiology and the Cancer Center, Medical college of Wisconsin, Milwaukee, WI 53226,USA; Department of Pharmacology and Toxicology and the Cancer Center, Medical college of Wisconsin, Milwaukee, WI 53226, USA.
Received August 3, 2010; accepted September 15, 2010; Epub: September 20, 2010; Published January 1, 2011
Abstract: Genes differentially expressed by tumor cells represent promising drug targets for anti-cancer therapy. Such candidate genes need to be validated in appropriate animal models. This study examined the suitability of rodent models of bladder cancer in B6D2F1 mice and Fischer-344 rats to model clinical bladder cancer specimens in humans. Using a global gene expression approach cross-species analysis showed that 13~34% of total genes in the genome were differentially expressed between tumor and normal tissues in each of five datasets from humans, rats, and mice. About 20% of these DEGs overlapped among species, corresponding to 2.6 to 4.8% of total genes in the genome. Several genes were consistently dysregulated in bladder tumors in both humans and rodents. Notably, CNN1, MYL9, PDLIM3, ITIH5, MYH11, PCP4 and FMO5 were found to commonly down-regulated; while TOP2A, CCNB2, KIF20A and RRM2 were up-regulated. These genes are likely to have conserved functions contributing to bladder carcinogenesis. Gene enrichment analysis detected a number of molecular pathways, commonly activated in both humans and rodent bladder cancer. These pathways affect the cell cycle, HIF-1 and MYC expression, and regulation of apoptosis. We also compared expression changes at mRNA and protein levels in the rat model and identified several genes/proteins exhibiting concordant changes in bladder tumors, including ANXA1, ANXA2, CA2, KRT14, LDHA, LGALS4, SERPINA1, KRT18 and LDHB. In general, rodent models of bladder cancer represent the clinical disease to an extent that will allow successful mining of target genes and permit studies on the molecular mechanisms of bladder carcinogenesis. (AJTR1008001).
Key words: Human bladder cancer, rodent models, gene expression, proteomics, and cross-species comparison
Address all correspondence to: Ming You, MD, PhD Department of Surgery and the Alvin J. Siteman Cancer Center Washington University School of Medicine Campus Box 8109, 660 S. Euclid Ave. St. Louis, MO 63110 Phone: 314-362-9294 Fax: 314-362-9366 E-mail: email@example.com