Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://hdl.handle.net/11449/150007 |
Resumo: | Colorectal cancer (CRC) is associated with pathogens such as Fusobacterium nucleatum (Fn), which can provide a favorable microenvironment for tumorigenesis due to inflammatory changes. In order to understand the effect of Fn on the microenvironment of intestinal lesions, the relative quantification (RQ) of this bacterium was evaluated in samples of colorectal adenoma tissue (CRA) and CCR, as well as its correlation with the mRNA expression of inflammatory mediators (TLR2, TLR4, NFKB1, TNF, IL1B, IL6 e IL8), and microRNAs (miR-21-3p, miR-22-3p, miR-28-5p, miR-34a-5p e miR-135b-5p) involved in the inflammatory response and carcinogenesis. A miRNA: mRNA interaction network was also delineated to aid in the understanding of miRNA participation in the carcinogenic process. DNA and RNA were extracted from 27 fresh tissue samples of CRA and 43 of CRC and their respective adjacent normal ones. Fn and mRNA levels of the inflammatory mediators and miRNAs were quantified by quantitative real-time PCR (qPCR). Elevated levels of Fn were detected in CRA (RQ=5.64 and more markedly in CRC (RQ=8.67). High mRNA expression of TLR4, IL1B, IL8 and miR-135b in CRA, and of TLR2, IL1B, IL6, IL8, miR-34a and miR-135b in CRC were observed in comparison with their respective normal tissues. In addition, miR-22 and miR-28 were found downregulated in CRC. The mRNA expression of IL1B, IL6, IL8 and miR-22 was positively correlated with the quantification of Fn in CRC. The mRNA expression of miR-135b and TNF was inversely correlated in tumor tissue, suggesting TNF as a possible target of this miRNA in CRC. The interaction miRNA:mRNA network suggest that the increased expression of miR-34a in CRC can regulates TLR4 favoring the recognition of Fn by TLR2, which is upregulated in tumor tissue, whereas in CRA this recognition must be mainly via TLR4. These results suggest an increase in Fn colonization during the progression of the adenoma-adenocarcinoma pathway, indicating it as a risk factor for colorectal carcinogenesis. The abundance of this bacterium in the gut promotes increased expression of inflammatory mediators such as IL1B, IL6 and IL8 through their recognition by TLR2 or TLR4, depending on the interaction with differentially expressed miRNAs. |
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Repositório Institucional da UNESP |
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Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretalEvaluation of the influence of Fusobacterium nucleatum on the modulation of cytokines and microRNAs in adenoma and colorectal cancerCâncer colorretalAdenoma colorretalFusobacterium nucleatumInflamaçãoCitocinasMicroRNAsColorectal cancerColorectal adenomaInflammationCytokinesColorectal cancer (CRC) is associated with pathogens such as Fusobacterium nucleatum (Fn), which can provide a favorable microenvironment for tumorigenesis due to inflammatory changes. In order to understand the effect of Fn on the microenvironment of intestinal lesions, the relative quantification (RQ) of this bacterium was evaluated in samples of colorectal adenoma tissue (CRA) and CCR, as well as its correlation with the mRNA expression of inflammatory mediators (TLR2, TLR4, NFKB1, TNF, IL1B, IL6 e IL8), and microRNAs (miR-21-3p, miR-22-3p, miR-28-5p, miR-34a-5p e miR-135b-5p) involved in the inflammatory response and carcinogenesis. A miRNA: mRNA interaction network was also delineated to aid in the understanding of miRNA participation in the carcinogenic process. DNA and RNA were extracted from 27 fresh tissue samples of CRA and 43 of CRC and their respective adjacent normal ones. Fn and mRNA levels of the inflammatory mediators and miRNAs were quantified by quantitative real-time PCR (qPCR). Elevated levels of Fn were detected in CRA (RQ=5.64 and more markedly in CRC (RQ=8.67). High mRNA expression of TLR4, IL1B, IL8 and miR-135b in CRA, and of TLR2, IL1B, IL6, IL8, miR-34a and miR-135b in CRC were observed in comparison with their respective normal tissues. In addition, miR-22 and miR-28 were found downregulated in CRC. The mRNA expression of IL1B, IL6, IL8 and miR-22 was positively correlated with the quantification of Fn in CRC. The mRNA expression of miR-135b and TNF was inversely correlated in tumor tissue, suggesting TNF as a possible target of this miRNA in CRC. The interaction miRNA:mRNA network suggest that the increased expression of miR-34a in CRC can regulates TLR4 favoring the recognition of Fn by TLR2, which is upregulated in tumor tissue, whereas in CRA this recognition must be mainly via TLR4. These results suggest an increase in Fn colonization during the progression of the adenoma-adenocarcinoma pathway, indicating it as a risk factor for colorectal carcinogenesis. The abundance of this bacterium in the gut promotes increased expression of inflammatory mediators such as IL1B, IL6 and IL8 through their recognition by TLR2 or TLR4, depending on the interaction with differentially expressed miRNAs.O câncer colorretal (CCR) está associado à patógenos como Fusobacterium nucleatum (Fn), que podem proporcionar um microambiente favorável para a tumorigênese em decorrência de alterações inflamatórias. Visando compreender o efeito de Fn no microambiente de lesões intestinais, avaliou-se a quantificação relativa (RQ) dessa bactéria em amostras de tecido de adenoma colorretal (ACR) e CCR, bem como sua correlação com a expressão de RNAm de mediadores inflamatórios (TLR2, TLR4, NFKB1, TNF, IL1B, IL6 e IL8) e de microRNAs (miRNAs) (miR-21-3p, miR-22-3p, miR-28-5p, miR-34a-5p e miR-135b-5p) envolvidos na resposta inflamatória e carcinogênese. Também delineou-se uma rede de interação miRNA:RNAm para auxiliar na compreensão da participação dos miRNAs no processo carcinogênico. Foram extraídos o DNA e o RNA de 27 amostras de tecido fresco de ACR e 43 de CCR e suas respectivas normais adjacentes. Os níveis de DNA de Fn e de RNAm dos mediadores inflamatórios e miRNAs foram quantificados por PCR quantitativo em tempo real (qPCR). Níveis elevados de Fn foram detectados em ACR (RQ=5,64) e mais acentuadamente em CCR (RQ=8,67). Observou-se expressão elevada do RNAm de TLR4, IL1B, IL8 e miR-135b em ACR, e de TLR2, IL1B, IL6, IL8, miR-34a e miR-135b em CCR em comparação com seus respectivos tecidos normais. Além disso, miR-22 e miR-28 foram encontrados com expressão reduzida em CCR. A expressão de RNAm de IL1B, IL6, IL8 e miR-22 foi positivamente correlacionada com a quantificação de Fn em CCR. A expressão de RNAm de miR-135b e TNF foi inversamente correlacionada no tecido tumoral, sugerindo TNF como um possível alvo deste miRNA em CCR. As interações miRNA:RNAm sugerem que a expressão aumentada de miR-34a em CCR regula TLR4 favorecendo o reconhecimento de Fn por TLR2, que encontra-se mais expresso no tecido tumoral, enquanto em ACR este reconhecimento deve ser principalmente via TLR4. Esses resultados sugerem um aumento da colonização de Fn durante a progressão da via adenoma-adenocarcinoma indicando-a como um fator de risco para a carcionogênese colorretal. A abundância dessa bactéria no intestino promove o aumento da expressão de mediadores inflamatórios como IL1B, IL6 e IL8 através do seu reconhecimento por TLR2 ou TLR4, conforme a interação com miRNAs diferentemente expressos.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Estadual Paulista (Unesp)Silva, Ana Elizabete [UNESP]Hughes, David J.Universidade Estadual Paulista (Unesp)Proença, Marcela Alcântara [UNESP]2017-03-29T19:52:57Z2017-03-29T19:52:57Z2017-03-03info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/11449/15000700088316433004153023P5porinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESP2023-10-17T06:07:14Zoai:repositorio.unesp.br:11449/150007Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T15:10:36.412716Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal Evaluation of the influence of Fusobacterium nucleatum on the modulation of cytokines and microRNAs in adenoma and colorectal cancer |
title |
Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal |
spellingShingle |
Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal Proença, Marcela Alcântara [UNESP] Câncer colorretal Adenoma colorretal Fusobacterium nucleatum Inflamação Citocinas MicroRNAs Colorectal cancer Colorectal adenoma Inflammation Cytokines |
title_short |
Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal |
title_full |
Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal |
title_fullStr |
Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal |
title_full_unstemmed |
Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal |
title_sort |
Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal |
author |
Proença, Marcela Alcântara [UNESP] |
author_facet |
Proença, Marcela Alcântara [UNESP] |
author_role |
author |
dc.contributor.none.fl_str_mv |
Silva, Ana Elizabete [UNESP] Hughes, David J. Universidade Estadual Paulista (Unesp) |
dc.contributor.author.fl_str_mv |
Proença, Marcela Alcântara [UNESP] |
dc.subject.por.fl_str_mv |
Câncer colorretal Adenoma colorretal Fusobacterium nucleatum Inflamação Citocinas MicroRNAs Colorectal cancer Colorectal adenoma Inflammation Cytokines |
topic |
Câncer colorretal Adenoma colorretal Fusobacterium nucleatum Inflamação Citocinas MicroRNAs Colorectal cancer Colorectal adenoma Inflammation Cytokines |
description |
Colorectal cancer (CRC) is associated with pathogens such as Fusobacterium nucleatum (Fn), which can provide a favorable microenvironment for tumorigenesis due to inflammatory changes. In order to understand the effect of Fn on the microenvironment of intestinal lesions, the relative quantification (RQ) of this bacterium was evaluated in samples of colorectal adenoma tissue (CRA) and CCR, as well as its correlation with the mRNA expression of inflammatory mediators (TLR2, TLR4, NFKB1, TNF, IL1B, IL6 e IL8), and microRNAs (miR-21-3p, miR-22-3p, miR-28-5p, miR-34a-5p e miR-135b-5p) involved in the inflammatory response and carcinogenesis. A miRNA: mRNA interaction network was also delineated to aid in the understanding of miRNA participation in the carcinogenic process. DNA and RNA were extracted from 27 fresh tissue samples of CRA and 43 of CRC and their respective adjacent normal ones. Fn and mRNA levels of the inflammatory mediators and miRNAs were quantified by quantitative real-time PCR (qPCR). Elevated levels of Fn were detected in CRA (RQ=5.64 and more markedly in CRC (RQ=8.67). High mRNA expression of TLR4, IL1B, IL8 and miR-135b in CRA, and of TLR2, IL1B, IL6, IL8, miR-34a and miR-135b in CRC were observed in comparison with their respective normal tissues. In addition, miR-22 and miR-28 were found downregulated in CRC. The mRNA expression of IL1B, IL6, IL8 and miR-22 was positively correlated with the quantification of Fn in CRC. The mRNA expression of miR-135b and TNF was inversely correlated in tumor tissue, suggesting TNF as a possible target of this miRNA in CRC. The interaction miRNA:mRNA network suggest that the increased expression of miR-34a in CRC can regulates TLR4 favoring the recognition of Fn by TLR2, which is upregulated in tumor tissue, whereas in CRA this recognition must be mainly via TLR4. These results suggest an increase in Fn colonization during the progression of the adenoma-adenocarcinoma pathway, indicating it as a risk factor for colorectal carcinogenesis. The abundance of this bacterium in the gut promotes increased expression of inflammatory mediators such as IL1B, IL6 and IL8 through their recognition by TLR2 or TLR4, depending on the interaction with differentially expressed miRNAs. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-03-29T19:52:57Z 2017-03-29T19:52:57Z 2017-03-03 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/11449/150007 000883164 33004153023P5 |
url |
http://hdl.handle.net/11449/150007 |
identifier_str_mv |
000883164 33004153023P5 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) |
publisher.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1808128474499514368 |