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

Heihachiro Nishimura,Takashi Nakanishi,Nobuhiko Ebisutani,Xuan Wang,Hirokazu Fukui,Tadayuki Oshima,Hiroto Miwa,Seiichi Hirota,Toshihiko Tomita

doi:10.3390/pathogens10040434

Abstract

Although sessile serrated adenoma/polyps (SSA/Ps) may arise through a pathway different from the traditional adenoma–carcinoma sequence, details of SSA/P tumorigenesis still remain unclear. Fusobacterium nucleatum (Fn) is frequently detected in colorectal cancer (CRC) tissues and may play a pivotal role in colorectal carcinogenesis. Here, we investigated the relationship between Fn and the β-catenin/REG Iα axis in SSA/Ps and their involvement in the proliferation of these lesions. Fn was detected in SSA/Ps by fluorescence in situ hybridization using a Fn-targeted probe, and expression of β-catenin, REG Iα and Ki67 was examined using immunohistochemistry. Sixteen of 30 SSA/P lesions (53.3%) were positive for Fn. Eighteen SSA/P lesions (60%) showed β-catenin immunoreactivity in the tumor cell nuclei. A significant majority of Fn-positive lesions showed nuclear expression of β-catenin (87.5%) and higher REG Iα scores and Ki67 labeling indices relative to Fn-negative lesions. The SSA/P lesions expressing β-catenin in nuclei had significantly higher REG Iα scores and Ki67 labeling indices than those expressing β-catenin on cytomembranes. The REG Iα score was positively correlated with the Ki67 labeling index in SSA/P lesions. The treatment with Wnt agonist SKL2001 promoted nuclear β-catenin translocation and enhanced REG Ia expression in Caco2 cells. Fn may play a role in the proliferation of SSA/P lesions through promotion of β-catenin nuclear translocation and REG Iα expression.

Highlights

It is widely accepted that colorectal cancers (CRCs) arise from adenomas [1], the pathway responsible has recently been shown to be far from simple [2]
We evaluated the density of the signal population in both sessile serrated adenoma/polyps (SSA/Ps) lesions and in the adjacent non-neoplastic regions
As the density in the non-neoplastic regions was 0.81 ± 0.15, we considered any SSA/P lesion to be positive for Fusobacterium nucleatum (Fn) if the signal density was more than 3.0

Summary

Introduction

It is widely accepted that colorectal cancers (CRCs) arise from adenomas [1], the pathway responsible has recently been shown to be far from simple [2]. SSA/Ps lesions show highlabeling index for Ki67 expression [5], suggesting that those lesions have high ability in cell proliferation These morphologic and genetic alterations are quite different from those in conventional adenomas, from which CRCs arise through accumulation of APC, KRAS and p53 mutations in multiple steps [1]. Among various candidate pathogenic bacteria, Fusobacterium nucleatum (Fn) has been gathering the most attention, since numerous studies have reported that a higher abundance of Fn is associated with a more advanced stage, a higher risk of recurrence, and shorter survival in patients with CRC [7,8,9] It is still debatable whether Fn directly plays a role in the pathogenesis of CRC patients Fn may promote colorectal carcinogenesis by activating β-catenin signaling in vitro experiments [10,11]

Methods

Results

Conclusion