Relationship between Fusobacterium nucleatum,inflammatory mediators and microRNAs in colorectal carcinogenesis

作     者：Marcela Alcantara Proenca Joice Matos Biselli Maysa Succi Fábio Eduardo Severino Gustavo Noriz Berardinelli Alaor Caetano Rui Manuel Reis David J Hughes Ana Elizabete Silva 

作者机构：Department of BiologyUNESPUniv. Estadual PaulistaCampus of Sao Jose do Rio PretoSao Jose do Rio PretoSao Paulo 15054-000Brazil Department of Surgery and OrthopedicsFaculty of MedicineUNESPUniv. Estadual PaulistaCampus of BotucatuBotucatuSao Paulo 18618-687Brazil Endoscopy Center of Rio PretoSao Jose do Rio PretoSao Paulo 15015-700Brazil Molecular Oncology Research CenterBarretos Cancer HospitalBarretosSao Paulo 14784-400Brazil Life and Health Sciences Research InstituteUniversity of MinhoCampus GualtarBraga 4710-057Portugal ICVS/3B’s-PT Government Associate LaboratoryCampus GualtarBraga 4710-057Portugal Cancer Biology and Therapeutics GroupUCD Conway InstituteUniversity College DublinDublin D04 V1W8Ireland 

出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)

年 卷 期：2018年第24卷第47期

页      面：5351-5365页

核心收录：

学科分类：10[医学] 

基　　金：Supported by Sao Paulo Research Foundation(FAPESP),No.2012/15036-8 National Council for Scientific and Technological Development(CNPq),No.474.776/2013-1 the Sao Paulo Research Foundation(FAPESP,NO.2015/21464-0)for the support for English revision the Coordination for the Improvement of Higher Education Personnel(CAPES)for the doctoral scholarship the National Council for Scientific and Technological Development(CNPq,NO.310120/2015-2)for the productivity research scholarship 

主　　题：Colorectal cancer Colorectal adenoma Fusobacterium nucleatum Inflammation Cytokines MicroRNAs 

摘      要：AIM To examine the effect of Fusobacterium nucleatum(F. nucleatum) on the microenvironment of colonic neoplasms and the expression of inflammatory mediators and microRNAs(miRNAs).METHODS Levels of F. nucleatum DNA, cytokine gene mRNA(TLR2, TLR4, NFKB1, TNF, IL1 B, IL6 and IL8), and potentially interacting miRNAs(miR-21-3p, miR-22-3p, mi R-28-5p, miR-34a-5p, miR-135b-5p) were measured by quantitative polymerase chain reaction(qPCR) TaqMan? assays in DNA and/or RNA extracted from the disease and adjacent normal fresh tissues of 27 colorectal adenoma(CRA) and 43 colorectal cancer(CRC) patients. KRAS mutations were detected by direct sequencing and microsatellite instability(MSI) status by multiplex PCR. Cytoscape v3.1.1 was used to construct the postulated miRNA:mRNA interaction *** Overabundance of F. nucleatum in neoplastic tissue compared to matched normal tissue was detected in CRA(51.8%) and more markedly in CRC(72.1%). We observed significantly greater expression of TLR4, IL1 B, IL8, and miR-135 b in CRA lesions and TLR2, IL1 B, IL6, IL8, mi R-34 a and miR-135 b in CRC tumours compared to their respective normal tissues. Only two transcripts for miR-22 and miR-28 were exclusively downregulated in CRC tumour samples. The mRNA expression of IL1 B, IL6, IL8 and miR-22 was positively correlated with F. nucleatum quantification in CRC tumours. The mRNA expression of miR-135 b and TNF was inversely correlated. The miRNA:mRNA interaction network suggested that the upregulation of miR-34 a in CRC proceeds via a TLR2/TLR4-dependent response to F. nucleatum. Finally, KRAS mutations were more frequently observed in CRC samples infected with F. nucleatum and were associated with greater expression of miR-21 in CRA, while IL8 was upregulated in MSI-high *** Our findings indicate that F. nucleatum is a risk factor for CRC by increasing the expression of inflammatory mediators through a possible mi RNA-mediated activation of TLR2/TLR4.