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Effects of colonic serotonergic activity on DNA damage inducing colon carcinogenesis

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Author(s):
Juliana Yumi Sakita
Total Authors: 1
Document type: Master's Dissertation
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
Defense date:
Examining board members:
Vinicius Kannen Cardoso; Cláudia Helena Pellizzon; Wilson Araújo da Silva Junior; Jeremy Andrew Squire
Advisor: Vinicius Kannen Cardoso
Abstract

Serotonin (5-HT) activity may impact on the development of colorectal cancer. However, details of this process remain unknown. Tryptophan hydroxylase 1 knockout (Tph1KO) mice fail to synthesize 5-HT and provide an appropriate model system to study the role of this neurohormone in colorectal carcinogenesis. Tph1KO mice have a decreased development of allograft tumors and colitis-induced colorectal tumors. However, colorectal carcinogen treatment led to increased tumor numbers, with high DNA damage intensity in the colonic stem cell niche. It was related to decreased numbers of enteroendocrine cells but an increase in the goblet cell population. Indeed, 5-HT synthesis promoted O-6-methylguanine-DNA methyltransferase activity in response to azoxymethane before activating ataxia telangiectasia and Rad3 related (ATR) and transformation related protein 53 (Trp53) expression. Radiation-induced DNA damage could be rescued by 5-hydroxytryptophan. The protective role of 5-HT was confirmed in transgenic mice with intestine-specific loss of Tph1 expression. This investigation reveals a protective role of 5-HT synthesis against the development of colorectal carcinogenesis. (AU)

FAPESP's process: 17/01260-7 - Effects of colonic serotonergic activity on DNA damage inducing carcinogenesis Colon
Grantee:Juliana Yumi Sakita Ozawa
Support Opportunities: Scholarships in Brazil - Master