Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer

Abstract

BackgroundEmerging evidence suggests a potential relationship between gut microbiota and the host response to chemotherapeutic drugs including 5-fluorouracil (5-Fu). Fusobacterium nucleatum (Fn) has been linked to the initiation and progression of colorectal cancer (CRC). Unfortunately, little was known about the relationship between Fn infection and chemotherapeutic efficacy. Here, we investigate the potential relationship between Fn infection and chemotherapeutic efficacy of 5-Fu in CRC.MethodsDifferentially expressed genes of CRC cell lines induced by Fn infection were analyzed based on a whole genome microarray analysis Then, we explored the relationship between upregulation of BIRC3 induced by Fn infection and chemoresistance to 5-Fu in vitro and in vivo. Furthermore, we dissected the mechanisms involved in Fn-induced BIRC3 expression. Finally, we investigated the clinical relevance of Fn infection, BIRC3 protein expression and chemoresistance to 5-Fu treatment in CRC patients.ResultsBIRC3 was the most upregulated gene induced by Fn infection via the TLR4/NF-κB pathway in CRC cells; Fn infection reduced the chemosensitivity of CRC cells to 5-Fu through upregulation of BIRC3 in vitro and in vivo. High Fn abundance correlated with chemoresistance in advanced CRC patients who received standard 5-Fu-based adjuvant chemotherapy after radical surgery.ConclusionsOur evidence suggests that Fn and BIRC3 may serve as promising therapeutic targets for reducing chemoresistance to 5-Fu treatment in advanced CRC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0985-y) contains supplementary material, which is available to authorized users.

Fusobacterium nucleatum Accelerates the Progression of Colitis-Associated Colorectal Cancer by Promoting EMT

“…Previous studies have reported that F. nucleatum contributes to the progression of colitis by damaging the integrity of colon epithelium and downregulating intercellular adhesion molecules, and that it also induces characteristic changes in macrophages in the colorectal tumor microenvironment [ 28 ]. Studies on the development and progression of CRC have shown that F. nucleatum promotes tumor formation as well as chemoresistance [ 29 ]. Although numerous works have reported the importance of F. nucleatum in the pathogenesis of UC and CRC, the role of F. nucleatum in the pathogenesis of CAC [ 30 ], which is the product of the close relationship between UC and CRC, remains unclear.…”

Time-Course Transcriptome Analysis of Gingiva-Derived Mesenchymal Stem Cells Reveals That Fusobacterium nucleatum Triggers Oncogene Expression in the Process of Cell Differentiation

“…F. nucleatum promotes colorectal cancer cell proliferation and tumorigenesis by activating Tolllike receptor 4(TLR4) signaling, which upregulates nuclear factor-κB, as indicated by increased MicroRNA-21 expression or the TLR4/p-PAK1/p-β-catenin S675-cascade signaling pathway (Yang et al, 2017;Wu et al, 2018). F. nucleatum promotes chemoresistance by upregulating BIRC3 expression and modulating autophagy in colorectal cancer (Yu et al, 2017;Zhang et al, 2019). In addition, in esophageal cancer tissue, F. nucleatum was associated with shorter times of survival for patients, which suggested the F. nucleatum has the potential to become as a prognostic biomarker (Yamamura et al, 2016).…”

Identification of Intestinal Flora-Related Key Genes and Therapeutic Drugs in Colorectal Cancer

“…Previous studies have con rmed that alteration of intestinal ora can promote CRC development by inducing in ammation, immune suppression, and attacking the gut barrier system [19][20][21]. Moreover, intestinal ora has been proven to promote tumorigenesis and chemoresistance of CRC via regulating gene expression [22][23][24]. Therefore, the mechanism of intestinal ora contributing to the development of CRC is complex and multifaceted.…”