title: A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer.
abstract: Comparing normal colorectal mucosa and adenomas focusing on deregulated pathways obtains insight into the biological processes of early colorectal carcinogenesis. Publicly available microarray expression data from 26 normal mucosa and 47 adenoma samples were analyzed. Biological pathways enriched in adenomas were identified with Gene Set Enrichment Analysis (GSEA). The analysis revealed 10, 11 and 16 gene sets distinguishing adenomas from normal mucosa according to Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Map Annotator and Pathway Profiler (GenMAPP) and Biocarta databases, respectively. Biological pathways known to be involved in colon carcinogenesis such as cell cycle (P=0.002) and Wnt signaling (P=0.007) were enriched in adenomas. In addition, we found enrichment of novel pathways such as retinoblastoma (Rb) pathway (P=0.002), Src pathway (P=0.004), folate biosynthesis (P=0.019) and Hedgehog signaling (P=0.037) in adenomas. Microarray results for Rb and Src pathway genes were validated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on mRNA isolated from an independent set of adenoma and normal colon samples. A high correlation between microarray data and qRT-PCR expression data was found. The relevance of targeting of identified pathways was shown using the Rb pathway inhibitors roscovitine and PD-0332991 and the Src pathway inhibitor dasatinib. All inhibitors used induced cell growth reduction in adenoma cells. This study shows a bioinformatical and functional approach leading to potentially new options for chemoprevention of colorectal cancer.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: D M
authors.initials: DM
authors.lastname: Heijink
authors.forename: R S N
authors.initials: RS
authors.lastname: Fehrmann
authors.forename: E G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: J J
authors.initials: JJ
authors.lastname: Koornstra
authors.forename: D
authors.initials: D
authors.lastname: Oosterhuis
authors.forename: A G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: J H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: S
authors.initials: S
authors.lastname: de Jong
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000517:prevention & control; D016477:Artifacts; D045744:Cell Line, Tumor; D018890:Chemoprevention / Q000379:methods*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000517:prevention & control*; D019295:Computational Biology / Q000379:methods* / Q000592:standards; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011786:Quality Control; D012015:Reference Standards; D015203:Reproducibility of Results; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016160:Retinoblastoma Protein; D016392:Proto-Oncogene Proteins pp60(c-src)