Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats

Toxicology and Applied Pharmacology. 2006 Feb 3. [Link]

Yongbaek Kim^a, Thai-Vu Ton^a, Anthony B. DeAngelo^d, Kevin Morgan^e, Theodora R. Devereux^b, Colleen Anna^b, Jennifer B. Collins^c, Richard S. Paules^c, Lynn M. Crosby^f and Robert C. Sills^a

^aEnvironmental Toxicology Program, National Institute of Environmental Health Sciences, MD B3-08, 111 Alexander Drive, Research Triangle Park, NC 27709, USA
^bEnvironmental Carcinogenesis Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
^cMicroarray Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
^dEnvironmental Protection Agency, Research Triangle Park, NC 27709, USA
^eAventis, Bridgewater, NJ 08807, USA
^fWyeth Research, Chazy, NY 12921, USA

Abstract

This study was performed to characterize the gene expression profile and to identify the major carcinogenic pathways involved in rat peritoneal mesothelioma (RPM) formation following treatment of Fischer 344 rats with o-nitrotoluene (o-NT) or bromochloracetic acid (BCA). Oligo arrays, with over 20,000 target genes, were used to evaluate o-NT- and BCA-induced RPMs, when compared to a non-transformed mesothelial cell line (Fred-PE). Analysis using Ingenuity Pathway Analysis software revealed 169 cancer-related genes that were categorized into binding activity, growth and proliferation, cell cycle progression, apoptosis, and invasion and metastasis. The microarray data were validated by positive correlation with quantitative real-time RT-PCR on 16 selected genes including igf1, tgfb3 and nov. Important carcinogenic pathways involved in RPM formation included insulin-like growth factor 1 (IGF-1), p38 MAPkinase, Wnt/β-catenin and integrin signaling pathways. This study demonstrated that mesotheliomas in rats exposed to o-NT- and BCA were similar to mesotheliomas in humans, at least at the cellular and molecular level.

Keywords: Rat; Mesotheliomas; Bromochloroacetic acid (BCA); o-Nitrotolulene; Carcinogenesis; Microarray

Abbreviations: BCA, bromochloroacetic acid; DNA, deoxyribose nucleic acid; F344, Fischer 344; H and E, hematoxylin and eosin; IGF, insulin-like growth factor; IPA, ingenuity pathway analysis; NTP, National Toxicology Program; o-NT, o-nitrotoluene; RNA, ribose nucleic acid; RPM, rat peritoneal mesothelioma; RT-PCR, reverse transcription polymerase chain reaction; SV40, simian virus 40; TGF, transforming growth factor