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

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Autor(es):
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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]
Número total de Autores: 19
Afiliação do(s) autor(es):
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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
Número total de Afiliações: 12
Tipo de documento: Artigo Científico
Fonte: JOURNAL OF PATHOLOGY; v. 249, n. 1, p. 102-113, SEP 2019.
Citações Web of Science: 0
Resumo

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)

Processo FAPESP: 17/01260-7 - Efeitos da atividade serotoninérgica colônica sobre o dano de DNA indutor da carcinogênese de cólon
Beneficiário:Juliana Yumi Sakita
Linha de fomento: Bolsas no Brasil - Mestrado
Processo FAPESP: 14/06428-5 - Como a sinalização serotoninérgica epitelial difere dos efeitos de sua síntese neural durante a inflamação associada ou não ao câncer de cólon
Beneficiário:Vinicius Kannen Cardoso
Linha de fomento: Auxílio à Pesquisa - Jovens Pesquisadores
Processo FAPESP: 15/01723-1 - Como a sinalização serotoninérgica epitelial difere dos efeitos de sua síntese neural durante a carcinogênese de cólon
Beneficiário:Vinicius Kannen Cardoso
Linha de fomento: Bolsas no Brasil - Jovens Pesquisadores
Processo FAPESP: 16/12619-3 - Efeitos da síntese epitelial de serotonina sobre o desenvolvimento da carcinogênese de cólon
Beneficiário:Bianca Gasparotto
Linha de fomento: Bolsas no Brasil - Mestrado