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Haplotype Insufficiency for Suppressor of Cytokine Signaling-2 Enhances Intestinal Growth and Promotes Polyp Formation in Growth Hormone-Transgenic Mice

Departments of Cell and Molecular Physiology (C.Z.M., N.M.R., J.G.S., C.K.T., K.K.M., P.K.L.) and Pathology (J.T.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and Cancer and Haematology Division (C.J.G.), The Walter and Eliza Hall Institute of Medical Research and the Cooperative Centre for Cellular Growth Factors, Parkville, Victoria 3050, Australia

Address all correspondence and requests for reprints to: Carmen Z. Michaylira, CB 7545, Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545. E-mail: carmen_michaylira{at}med.unc.edu.

GH may improve intestinal growth or function in patients with short bowel syndrome. Excessive trophic effects of GH or IGF-I may contribute to neoplastic growth or increased colorectal cancer risk in acromegaly. Identification of mechanisms that limit the tumorigenic potential of GH and IGF-I is desirable. Suppressor of cytokine signaling-2 (SOCS2) limits GH action on body and organ growth, but its role in GH action on intestine is unknown. We tested the hypothesis that SOCS2 limits GH-induced intestinal growth or neoplasia in vivo. GH-transgenic (GH-TG) mice were crossed with SOCS2 null mice to generate wild-type (WT) or transgenic (TG) mice with zero (HO-WT; HO-TG), one (HT-WT; HT-TG), or two (WT-WT; WT-TG) functional SOCS2 genes. No HO-TG mice were derived from crossbreeding. WT-WT, HT-WT, WT-TG, and HT-TG were compared. Body weight, small intestine and colon growth, and levels of jejunal IGF-I and sucrase-isomaltase mRNAs were assessed. Colon was analyzed for abnormal lesions. HT-WT did not differ from WT-WT. Compared with WT-TG, HT-TG had significantly increased body weight, small intestine growth, and local IGF-I expression and decreased sucrase-isomaltase expression. HT-TG colon spontaneously developed multiple hyperplastic and lymphoid polyps. GH-induced activation of STAT5 DNA binding activity was enhanced in intestine of SOCS2 null mice compared with WT control. Haplotype insufficiency for SOCS2 promotes trophic actions of GH in small intestine and promotes preneoplastic growth in colon during excess GH. Small variations in SOCS2 expression levels may significantly influence the outcome of therapeutic GH or acromegaly in intestine.

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				C. Z. Michaylira, J. G. Simmons, N. M. Ramocki, B. P. Scull, K. K. McNaughton, C. R. Fuller, and P. K. Lund Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo Am J Physiol Gastrointest Liver Physiol, September 1, 2006; 291(3): G472 - G481. [Abstract] [Full Text] [PDF]