Avaliação da influência de Fusobacterium nucleatum na modulação de citocinas e microRNAs em adenoma e câncer colorretal

• Ano de defesa: 2017
• Autor(a) principal: Proença, Marcela Alcântara [UNESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Estadual Paulista (Unesp)
• Palavras-chave em Português: Câncer colorretal; Adenoma colorretal; Fusobacterium nucleatum; Inflamação; Citocinas; MicroRNAs; Colorectal cancer; Colorectal adenoma; Inflammation; Cytokines
• Link de acesso: http://hdl.handle.net/11449/150007

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.