Endocrine Abstracts

Paracrine IGF-I expression in the colon is associated with elevations of tumourigenic genes

PA Kelly¹, BW Ogunkolade¹, PD Fairclough², SA Bustin³ & PJ Jenkins¹

¹Department of Endocrinology, Bart's and The London, Queen Mary's School of Medicine and Dentistry, University of London, London, United Kingdom; ²Department of Gastroenterology, Bart's and The London NHS Trust, London, London, United Kingdom; ³Department of Academic Surgery, Bart's and The London, Queen Mary's School of Medicine and Dentistry, University of London, London, United Kingdom.

Introduction: The GH/IGF-I axis is implicated in colorectal cancer development. We have previously shown regional variations of the GH/IGF-I axis, and other tumour associated genes between the rectum (RS) and caecum (C). Whether variations in the GH/IGF-I axis align with differing expression patterns is unknown.

Aim: To determine the association between colonic expression of the GH/IGF-I axis and that of tumour associated genes by region.

Methods: Ethics approval and consent were obtained from 26 patients for biopsies to be taken at colonoscopy from the rectosigmoid and caecum; patients with inflammation and neoplasia were excluded. Total RNA was extracted and mRNA levels of GH, GHR, IGF-I, IGF-IR, IGF-BP3, PCNA, c-myc, COX-2 and VEGF quantitated by real-time RT-PCR; results expressed as median mRNA copy number per microgram total RNA.

Results: The IGF-I gene was expressed in 14 of the rectosigmoid (p=0.002) and 9 of the caecal samples (p<0.0001), whereas all other genes were universally expressed, except 2 with absent caecal GHR, and one with absent caecal BP3. Those who expressed IGF-I at both regions (n=6) had increased expression vs those with IGF-I at neither (n=9) of [site]: IGF-IR [RS] 1.4 x10⁶ vs 8.3 x10⁵ (p=0.04); c-myc [RS] 4.1 x10⁷ vs 2.3 x10⁷ (p=0.02), c-myc [C] 3.5 x10⁷ vs 1.5 x10⁷ (p=0.02); PCNA [RS] 3.8 x10⁶ vs 8.0 x10⁶ (p=0.005); PCNA [C] 4.0 x10⁶ vs 3.8 x10⁵ (p=0.002). Comparing those with IGF-I expression in the sigmoid to those without, the following genes were present in greater copy number: Cox-2 1.8 x10⁶ vs 4.7 x10⁵ (p=0.02); c-myc 3.9 x10⁷ vs 2.1 x10⁷ (p=0.008); PCNA 2.4 x10⁶ vs 9.5 x10⁵ (p=0.04).

Conclusions: Local IGF-I expression is associated with elevated expression of tumour associated genes c-myc, COX-2, PCNA, and the IGF-1R. A pattern is identified which suggests an important role for paracrine/autocrine IGF-I in regulating the expression of the genes that dictate the balance between proliferation and apoptosis.

Endocrine Abstracts (2002) 4 P35