Gene expression profiling of the Inflammation-Dysplasia-Cancer sequence of Inflammatory Bowel Disease.

AA O'Riordan, BSc, a F Shanahan, MD, b, D. ODonoghue, MD, c JG Morgan, PhD, a.

a Department of Microbiology, University College Cork, Ireland, b Department of Medicine, Cork University Hospital, Ireland, c Department of Gastroenterology, St. Vincents Hospital, Dublin, Ireland.

Aims To apply gene array technology to establish gene expression profiles of the Inflammation-Dysplasia-Cancer Sequence in Inflammatory Bowel Disease (IBD). Methods Colonic biopsies from 6 Ulcerative Colitis (UC) patients with active disease of greater than 10 years were examined. These included 2 matched normal controls and 1 dysplasic sample. 1 matched normal and colorectal tumor and 1 unmatched normal were also sources of mRNA for 33P reverse transcription to cDNA and hybridised to Clontech Human 1.2 Cancer arrays. Results We confirmed, by gene array and cluster analysis, the upregulation of previously reported Neutrophil Gelatinase Associated Lipocalin (NGAL) and Matrix Metalloproteinase 14 (MMP-14). We also report the novel finding of the downregulation of a Heat Shock Chaperone 70 interacting protein (HIP) and suggest a role for the downregulation of a UDP glucouronosyltransferase (UDPGT). Conclusion IBD patients of 10 years disease duration or greater have a higher incidence of colorectal cancer development. Dysplasia can be present in mucosa that appears normal at colonoscopy and may not always be detected. These data could prove to be useful markers of those individuals with active disease and those at higher risk of cancer progression. MMP-14 and NGAL show upregulation of expression. Their association with neoplasia may be useful as markers of early dysplasia. We report the downregulation of HSC70 interacting protein (HIP) in UC tissue. HIP is a suggested tumor suppressor whose expression is downregulated in human colorectal carcinomas. We also confirm downregulation of a detoxification UDPGT. Without detoxification, the inflammatory responses and their effects may be self-perpetuating.

KEY WORDS: Gene Expression, Profiling, Oligonucleotide Array.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Carcinogenesis.