Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats

• Published in: BMC cancer 2010-05, Vol.10 (1), p.194-194, Article 194
• Main Authors: Femia, Angelo Pietro, Luceri, Cristina, Toti, Simona, Giannini, Augusto, Dolara, Piero, Caderni, Giovanna
• Format: Article
• Language: English
• Subjects: 1,2-Dimethylhydrazine; Adenocarcinoma - chemically induced; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Animals; Cell Transformation, Neoplastic - chemically induced; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Colon cancer; Colonic Neoplasms - chemically induced; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Comparative Genomic Hybridization; Development and progression; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Gene mutations; Gene Regulatory Networks; Health aspects; Hydrazine; Identification and classification; Immunohistochemistry; Male; Methyl groups; Oligonucleotide Array Sequence Analysis; Physiological aspects; Rats; Rats, Inbred F344; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-10-194

Azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats shares many phenotypical similarities with human sporadic colon cancer and is a reliable model for identifying chemopreventive agents. Genetic mutations relevant to human colon cancer have been described in this model, but comprehensive gene expression and genomic analysis have not been reported so far. Therefore, we applied genome-wide technologies to study variations in gene expression and genomic alterations in DMH-induced colon cancer in F344 rats. For gene expression analysis, 9 tumours (TUM) and their paired normal mucosa (NM) were hybridized on 4 x 44K Whole rat arrays (Agilent) and selected genes were validated by semi-quantitative RT-PCR. Functional analysis on microarray data was performed by GenMAPP/MappFinder analysis. Array-comparative genomic hybridization (a-CGH) was performed on 10 paired TUM-NM samples hybridized on Rat genome arrays 2 x 105K (Agilent) and the results were analyzed by CGH Analytics (Agilent). Microarray gene expression analysis showed that Defcr4, Igfbp5, Mmp7, Nos2, S100A8 and S100A9 were among the most up-regulated genes in tumours (Fold Change (FC) compared with NM: 183, 48, 39, 38, 36 and 32, respectively), while Slc26a3, Mptx, Retlna and Muc2 were strongly down-regulated (FC: -500; -376, -167, -79, respectively). Functional analysis showed that pathways controlling cell cycle, protein synthesis, matrix metalloproteinases, TNFalpha/NFkB, and inflammatory responses were up-regulated in tumours, while Krebs cycle, the electron transport chain, and fatty acid beta oxidation were down-regulated. a-CGH analysis showed that four TUM out of ten had one or two chromosomal aberrations. Importantly, one sample showed a deletion on chromosome 18 including Apc. The results showed complex gene expression alterations in adenocarcinomas encompassing many altered pathways. While a-CGH analysis showed a low degree of genomic imbalance, it is interesting to note that one of the alterations concerned Apc, a key gene in colorectal carcinogenesis. The fact that many of the molecular alterations described in this study are documented in human colon tumours confirms the relevance of DMH-induced cancers as a powerful tool for the study of colon carcinogenesis and chemoprevention.