Fusobacterium nucleatum Promotes the Progression of Colorectal Cancer Through Cdk5-Activated Wnt/β-Catenin Signaling

Abstract

Background/AimsGrowing evidence supports the direct link of Fusobacterium nucleatum with colorectal cancer (CRC). However, to date, the underlying mechanism of action remains poorly understood. In this study, we examined the effects of F. nucleatum on the progression of CRC and investigated whether cyclin-dependent kinase 5 (Cdk5) is involved in the effect through activating the Wnt/β-catenin signaling pathway.Materials and MethodsCRC tissues and matched histologically normal specimens were collected from patients who were diagnosed with CRC and underwent surgical treatment in our hospital between January 2018 and January 2019. Two human CRC cell lines, including DLD-1 and SW480, were utilized mainly for in vitro mechanistic investigations.ResultsThe abundance of F. nucleatum was significantly greater in CRC tissues than in cancer-free specimens, which was significantly correlated with the progression of CRC. In vitro investigations revealed that F. nucleatum significantly enhanced the proliferation and migration of CRC cells. Furthermore, F. nucleatum significantly induced the expression of Cdk5 and activation of the Wnt/β-catenin signaling pathway. Notably, knockdown of Cdk5 significantly abrogated the effects of F. nucleatum on cellular processes and Wnt/β-catenin signaling in relation to the progression of CRC.ConclusionThe results of this study demonstrate that F. nucleatum orchestrates a molecular network involving the direct role of Cdk5 in activating Wnt/β-catenin signaling to modulate CRC progression. Thus, in-depth investigations of F. nucleatum-associated molecular pathways may offer valuable insight into the pathogenesis of CRC, which may help further the development of treatment for this disease.

Fusobacterium Nucleatum Affects Cell Apoptosis by Regulating Intestinal Flora and Metabolites to Promote the Development of Colorectal Cancer

“…These ndings indicated that Fn could play an important role in the occurrence and development of CRC. We have con rmed in our previous work that at the cellular level, Fn promotes the progression of CRC through the Cdk5-activated Wnt/β-catenin signaling [19]. The experiments of the present study showed that the intestinal ora of mice given Fn gavage mainly included Firmicutes, Bacteroidetes, and Proteobacteria (Fig.…”

Role of the β-Catenin/REG Iα Axis in the Proliferation of Sessile Serrated Adenoma/Polyps Associated with Fusobacterium nucleatum

“…However, we preliminarily showed that nuclear β-catenin translocation by Wnt signaling activation may be closely associated with the enhancement of REG Iα expression in colon cancer cells in vitro. Interestingly, recent studies have suggested that Wnt signaling may be a key pathway for Fn-associated cell growth in colon cancer [11,47,48]. Thus, since REG Iα is able to function as a growth factor [25,26], we would like to speculate that Fn-associated β-catenin-nuclear translocation may play a role in the growth of SSA/P lesions, at least in part, via the growth-promoting effect of REG Iα protein.…”

Therapeutic strategies targeting Wnt/β‑catenin signaling for colorectal cancer (Review)

“…Certain studies have reported that Fusobacterium nucleatum , an anaerobic Gram-negative oral commensal bacterium, is important in CRC tumorigenesis and is often associated with metastasis, chemo-resistance and poor prognosis ( 53 , 155 - 157 ). A previous study has suggested that Fusobacterium nucleatum is present in CRC and adheres to and invades intestinal epithelial cells mainly via virulence factors, such as Fusobacterium adhesin A (FadA) ( 53 ).…”

“…However, Ma et al suggested that Fusobacterium nucleatum interacts with E-cadherin leading to EMT instead of β-catenin, which subsequently promotes the malignant phenotype of CRC cells ( 53 ). Another study showed that Fusobacterium nucleatum promotes CRC tumor growth via cyclin-dependent kinase 5 (Cdk5)-activated Wnt/β-catenin signaling and the Cdk5-mediated upregulation of β-catenin, cyclin D1 and c-Myc ( 157 ). Lactobacillus species, another bacterium, inhibits CRC progression via the upregulation of GSK-3β, as well as the downregulation of the Wnt/β-catenin-related genes, such as Axin-2, CTNNB1, cyclin D1, pygopus family PHD finger 2 and inhibitor of DNA binding 2 ( 158 ).…”