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Serotonin synthesis protects the mouse colonic crypt from DNA damage and colorectal tumorigenesis

Item Type:Article
Title:Serotonin synthesis protects the mouse colonic crypt from DNA damage and colorectal tumorigenesis
Creators Name:Sakita, J.Y. and Bader, M. and Santos, E.S. and Garcia, S.B. and Minto, S.B. and Alenina, N. and Brunaldi, M.O. and Carvalho, M.C. and Vidotto, T. and Gasparotto, B. and Martins, R.B. and Silva, W.A. and Brandão, M.L. and Leite, C.A. and Cunha, F.Q. and Karsenty, G. and Squire, J.A. and Uyemura, S.A. and Kannen, V.
Abstract:Serotonin (5-HT) signaling pathways are thought to be involved in colorectal tumorigenesis (CRT), but the role of 5-HT synthesis in the early steps of this process is presently unknown. In this study, we used carcinogen treatment in the tryptophan hydroxylase 1 knockout (Tph1KO) and transgenic (Tph1(fl/fl) Villin(Cre) mouse models defective in 5-HT synthesis to investigate the early mutagenic events associated with CRT. Our observations of the colonic crypt post-treatment followed a timeline designed to understand how disruption of 5-HT synthesis affects the initial steps leading to CRT. We found Tph1KO mice had decreased development of both allograft tumors and colitis-related CRT. Interestingly, carcinogenic exposure alone induced multiple colon tumors and increased cyclooxygenase-2 (Ptgs2) expression in Tph1KO mice. Deletion of interleukin 6 (Il6) in Tph1KO mice confirmed that inflammation was a part of the process. 5-HT deficiency increased colonic DNA damage but inhibited genetic repair of specific carcinogen-related damage, leading to CRT-related inflammatory reactions and dysplasia. To validate a secondary effect of 5-HT deficiency on another DNA repair pathway, we exposed Tph1KO mice to ionizing radiation and found an increase in DNA damage associated with reduced levels of ataxia telangiectasia and Rad3 related (Atr) gene expression in colonocytes. Restoring 5-HT levels with 5-hydroxytryptophan treatment decreased levels of DNA damage and increased Atr expression. Analysis of Tph1(fl/fl) Villin(Cre) mice with intestine-specific loss of 5-HT synthesis confirmed that DNA repair was tissue specific. In this study, we report a novel protective role for 5-HT synthesis that promotes DNA repair activity during the early stages of colorectal carcinogenesis.
Keywords:Intestines, Colon Cancer, Neuropeptide, γ-H2AX, DNA Damage Repair, Animals, Mice
Source:Journal of Pathology
Page Range:102-113
Date:September 2019
Official Publication:https://doi.org/10.1002/path.5285
PubMed:View item in PubMed

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