SUN-117 Growth Hormone-Releasing Hormone (GHRH) Deficiency Promotes Inflammation Associated Carcinogenesis

Abstract The somatotropic axis, in addition to its well-known metabolic and endocrine effects, plays a pivotal role in modulation of inflammation. Additionally, GH-releasing hormone (GHRH) has been involved in the regulation of the growth of various human tumors. In this work, we aimed to investigate the consequences of GHRH and GH deficiency on the development of inflammation-associated colon carcinogenesis in a mouse model of isolated GH deficiency due to generalized ablation of the GHRH gene [GHRH knock out (GHRHKO)]. Homozygous GHRHKO (-/-) male mice and wild type (C57/BL6, +/+) male mice as control group were used. After azoxymetane (AOM)/dextran sodium sulfate (DSS) treatment GHRHKO-/- mice displayed higher Disease Activity Index (DAI) score, and more marked weight loss compared to +/+ animals. Additionally, -/- mice showed a significant increase in total colonic tumors, in particular of large size and predominantly localized in distal colon. In colonic tissue of AOM/DSS-treated -/- mice we found the presence of invasive adenocarcinomas, dysplasia and colitis with mucosal ulceration. Conversely, AOM/DSS-treated +/+ mice showed only presence of adenomas, without invasion of sub-mucosa. Treatment with AOM/DSS significantly increased prostaglandin (PG)E2 and 8-iso-PGF2α levels along with cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α, nuclear factor kappa B (NFkB) and inducible nitric oxide synthase (iNOS) gene expression, in colon specimens of both groups. However, the degree of increase of all these parameters was more marked in -/- than +/+ mice. In conclusion, generalized GHRH ablation increases inflammatory response and colon carcinogenesis in male mice. Whether this results from lack of GH or GHRH remains to be established.