Endocrine Abstracts (2002) 3 OC15

Regional gene expression in the colon of patients with and without acromegaly

PA Kelly1, BW Ogunkolade1, PA Fairclough2, JP Monson1, AB Grossman1, GM Besser1, SA Bustin3 & PJ Jenkins1

1Department of Endocrinology, St. Bartholomew's Hospital, London, UK; 2Department of Gastroenterology, St. Bartholomew's Hospital, London, UK; 3Department of Academic Surgery, Bart's and the London School of Medicine, London, UK.

Background: Acromegalics are at increased risk of developing colorectal neoplasia with an increase of right-sided disease. Several genes are implicated in colorectal neoplasia including components of the GH/IGF-1 axis. It is unclear whether regional variations in neoplasia are explained by variations in local expression of these genes. Aims: To compare the expression of the components of the GH/IGF-1 axis and other putative genes between the left and right colon of patients with and without acromegaly, and to compare the regional expression between the groups.

Methods: Ethics Committee approval and informed consent was obtained from 24 acromegalics and 26 non-acromegalics undergoing surveillance colonoscopy. Pinch biopsies were taken from the left and right colon of each patient, and total RNA extracted and mRNA levels of GH, GH-R, IGF-I, IGF-IR, PCNA (proliferating cell nuclear antigen), c-myc, Cox-2, and VEGF quantitated by real-time RT-PCR, all results expressed as mRNA copy numbers per micrograms total RNA.

Results: Within individuals with and without acromegaly we find no difference in expression of IGF-1, GH, VEGF and PCNA. In non-acromegalics elevations in median copy number of the following genes are seen at the sigmoid v. caecum respectively; GHR 6.2 x105 v. 5.6 x104 (p<0.001), Cox-2 1.7 x10 6 v.6.2 x105 (p<0.001), and c-myc 3.4 x107 v. 1.9 x10 7 (p<0.05). In acromegalics, sigmoid v. caecum, respectivley, GHR 7.7 x106 v. 1.4 x105 (p<1 x10minus6), IGF-1R 1.6 x106 v. 6.2 x105 (p<0.001) and Cox-2 1.5 x106 v. 6.1 x105 (p<0.01). Comparing the two groups we find the GHR with significantly greater expression in the sigmoid of acromegalics v. non-acromegalics(p<0.001).

Conclusion: In the sigmoid elevated cox-2, c-myc and GHR in normals, and cox-2, GHR and IGF-1R in acromegalics may account for increased local neoplasia. The lack of any difference between groups of local IGF-1 supports the importance of endocrine IGF-1. The significance of increased GHR in the sigmoid of acromegalics and whether it indicates IGF-1 independent effects is to be determined.

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