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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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Sakita, Juliana Y. [1] ; Bader, Michael [2, 3, 4] ; Santos, Emerson S. [1] ; Garcia, Sergio B. [5] ; Minto, Stefania B. [5] ; Alenina, Natalia [6, 4] ; Brunaldi, Mariangela O. [5] ; Carvalho, Milene C. [7] ; Vidotto, Thiago [8] ; Gasparotto, Bianca [1] ; Martins, Ronaldo B. [9] ; Silva, Jr., Wilson A. [8] ; Brandao, Marcus L. [7] ; Leite, Caio A. [10] ; Cunha, Fernando Q. [10] ; Karsenty, Gerard [11] ; Squire, Jeremy A. [12, 8] ; Uyemura, Sergio A. [1] ; Kannen, Vinicius [1]
Total Authors: 19
Affiliation:
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[1] Univ Sao Paulo, Dept Toxicol Bromatol & Clin Anal, Ribeirao Preto - Brazil
[2] Charite Univ Med Berlin, Berlin - Germany
[3] BIH, Berlin - Germany
[4] Queens Univ, Dept Biomed & Mol Sci, Kingston, ON K7L 2V5 - Canada
[5] Univ Sao Paulo, Dept Pathol, Ribeirao Preto - Brazil
[6] St Petersburg State Univ, Inst Translat Biomed, St Petersburg - Russia
[7] Univ Sao Paulo, Fac Philosophy Sci & Letters, Ribeirao Preto - Brazil
[8] Univ Sao Paulo, Dept Genet, Ribeirao Preto - Brazil
[9] Univ Sao Paulo, Dept Cell & Mol Biol, Virol Res Ctr, Ribeirao Preto - Brazil
[10] Univ Sao Paulo, Dept Pharmacol, Ribeirao Preto - Brazil
[11] Columbia Univ, Dept Genet & Dev, New York, NY - USA
[12] Queens Univ, Dept Pathol & Mol Med, Kingston, ON - Canada
Total Affiliations: 12
Document type: Journal article
Source: JOURNAL OF PATHOLOGY; v. 249, n. 1, p. 102-113, SEP 2019.
Web of Science Citations: 0
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. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley \& Sons, Ltd. (AU)

FAPESP's process: 17/01260-7 - Effects of colonic serotonergic activity on DNA damage inducing carcinogenesis Colon
Grantee:Juliana Yumi Sakita
Support type: Scholarships in Brazil - Master
FAPESP's process: 14/06428-5 - Differentiating the effects of epithelial from the neural serotoninergic signalling during inflammation-related colon cancer
Grantee:Vinicius Kannen Cardoso
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 15/01723-1 - Differentiating the effects of epithelial from the neural serotonergic signalling during the development of colon carcinogenesis
Grantee:Vinicius Kannen Cardoso
Support type: Scholarships in Brazil - Young Researchers
FAPESP's process: 16/12619-3 - Serotonin epithelial synthesis impacts on the development of colon carcinogenesis
Grantee:Bianca Gasparotto
Support type: Scholarships in Brazil - Master