HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Jenkins, P J Articles by Bustin, S A Search for Related Content PubMed PubMed Citation Articles by Jenkins, P J Articles by Bustin, S A

Department of Endocrinology, William Harvey Research Institute, Barts and the London Queen Mary’s School of Dentistry, John Vane Building, Charterhouse Square, London EC1M 6BQ, UK
¹ Cancer Research UK, 61 Lincoln’s Inn Fields, London WC2A 3PX, UK
² Department of Academic Surgery, Barts and the London Queen Mary’s School of Dentistry, University of London, Turner Street, London E1 2AD, UK

(Requests for offprints should be addressed to P J Jenkins at the Department of Endocrinology, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK; Email: P.J.Jenkins{at}qmul.ac.uk)

IGF-binding protein-3 (IGFBP-3) has been reported to exert a protective influence on the pathogenesis of colorectal cancer. This may reflect its modulation of IGF-I bioactivity as well as IGF-I-independent effects on cell proliferation and apoptosis. Although local expression of IGF-I in the colon is increasingly recognised as having important regulatory consequences, the role of locally expressed IGFBP-3 remains unknown. The aims of the present study were: (i) to quantify and localise the expression of IGFBP-3 in human normal and malignant colon; (ii) to relate this expression to that of other components of the IGF-I axis; and (iii) to investigate the effects of IGFBP-3 on colonic epithelial cell proliferation and apoptosis. RNA was extracted from 46 paired samples of normal and malignant colonic tissue. IGFBP-3, IGF-I, IGF-I receptor and GH receptor mRNA levels were quantified using real-time RT-PCR. Laser-capture microdissection of the same samples was used to isolate mRNA from epithelium and stromal components and localise mRNA expression. Expression was confirmed at a protein level by immunohistochemistry. Human colorectal cancer HT-29 and CaCo-2 cells were cultured with IGFBP-3 (200 ng/ml), +/– IGF-I (20 ng/ml), +/– sodium butyrate (5 mM). Cell number was assessed by an MTS assay (a modification of the MTT assay), and apoptosis assessed by cell morphology and FACS analysis using both annexin and propidium iodide staining. UO146, a MAP kinase inhibitor, and wortmannin, an inhibitor of the phosphatidylinositol 3-kinase (PI-3K) pathway, were used to determine the contribution of these signalling pathways on the effects of IGFBP-3. IGFBP-3 mRNA was detected in all samples (mean copy number/µg total RNA in normal colon, 2.6 x 10⁶ compared with 1.3 x 10⁷ in the cancers; P<0.0001). Immunohistochemistry confirmed the expression and showed it to be equally distributed between epithelial and stromal components in normal tissue, but to be mainly restricted to the stromal component of malignant tissue. This differential expression was confirmed by RT-PCR of RNA from laser-capture microdissected samples. IGF-I mRNA was detected in 31 samples of normal colon; mean IGFBP-3 copy number was higher in the IGF-I-positive samples compared with IGF-I-negative samples. IGFBP-3 on its own induced apoptosis in HT-29 cells (P<0.001). Co-incubation of 200 ng/ml IGFBP-3 with butyrate (5 mM) resulted in the potentiation of its apoptosis (P<0.0001), which was not rescued by co-incubation with IGF-I (P<0.0001). The addition of UO126 caused a decrease in cell number and increased the effects of IGFBP-3. IGFBP-3 is differentially expressed between stromal and epithelial components of normal and malignant colon, which may reflect its pro-apoptotic, IGF-I-independent effect on colonic epithelial cells. These effects are mediated in part by the PI-3K pathway in contrast to the MAP kinase pathway used by IGF-I.

This article has been cited by other articles:

				K. MCCARTHY, C. LABAN, C.J MCVITTIE, W. OGUNKOLADE, S. KHALAF, S. BUSTIN, R. CARPENTER, and P.J. JENKINS The Expression and Function of IGFBP-3 in Normal and Malignant Breast Tissue Anticancer Res, October 1, 2009; 29(10): 3785 - 3790. [Abstract] [Full Text] [PDF]

				S. RESSLER, J. RADHI, T. AIGNER, C. LOO, W. ZWERSCHKE, and C. SERGI Insulin-like Growth Factor-binding Protein-3 in Osteosarcomas and Normal Bone Tissues Anticancer Res, July 1, 2009; 29(7): 2579 - 2587. [Abstract] [Full Text] [PDF]

				R. Gallego, J. Codony-Servat, X. Garcia-Albeniz, E. Carcereny, R. Longaron, A. Oliveras, M. Tosca, J. M. Auge, P. Gascon, and J. Maurel Serum IGF-I, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer Endocr. Relat. Cancer, March 1, 2009; 16(1): 311 - 317. [Abstract] [Full Text] [PDF]

				C. S. Fuchs, R. M. Goldberg, D. J. Sargent, J. A. Meyerhardt, B. M. Wolpin, E. M. Green, H. C. Pitot, and M. Pollak Plasma Insulin-like Growth Factors, Insulin-like Binding Protein-3, and Outcome in Metastatic Colorectal Cancer: Results from Intergroup Trial N9741 Clin. Cancer Res., December 15, 2008; 14(24): 8263 - 8269. [Abstract] [Full Text] [PDF]

				J. E. Mallewa, E. Wilkins, J. Vilar, M. Mallewa, D. Doran, D. Back, and M. Pirmohamed HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options J. Antimicrob. Chemother., October 1, 2008; 62(4): 648 - 660. [Abstract] [Full Text] [PDF]