1. Serotonin synthesis protects the mouse colonic crypt from DNA damage and colorectal tumorigenesis.
- Author
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Sakita JY, Bader M, Santos ES, Garcia SB, Minto SB, Alenina N, Brunaldi MO, Carvalho MC, Vidotto T, Gasparotto B, Martins RB, Silva WA Jr, Brandão ML, Leite CA, Cunha FQ, Karsenty G, Squire JA, Uyemura SA, and Kannen V
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins genetics, Ataxia Telangiectasia Mutated Proteins metabolism, CDX2 Transcription Factor genetics, CDX2 Transcription Factor metabolism, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Colon pathology, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Interleukin-6 deficiency, Interleukin-6 genetics, Mice, Knockout, Microfilament Proteins genetics, Microfilament Proteins metabolism, Precancerous Conditions genetics, Precancerous Conditions metabolism, Precancerous Conditions pathology, Signal Transduction, Time Factors, Tryptophan Hydroxylase deficiency, Tryptophan Hydroxylase genetics, Cell Transformation, Neoplastic metabolism, Colon metabolism, Colorectal Neoplasms prevention & control, DNA Damage, DNA Repair, Precancerous Conditions prevention & control, Serotonin biosynthesis
- 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 VillinCre ) 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 Tph1fl/fl VillinCre 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. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)- Published
- 2019
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