Vanillin Derivatives Reverse Fusobacterium nucleatum-Induced Proliferation and Migration of Colorectal Cancer Through E-Cadherin/β-Catenin Pathway.

Zhongkun Zhou,Wantong Ma,Kangjia Du,Xinrong Jiang,Yunhao Ma,Dekui Zhang,Rui Ji,Yiqing Wang,Peng Chen,Chi Ma,Rentao Zhang

doi:10.3389/fphar.2022.841918

Abstract

Colorectal cancer (CRC) is a common clinical malignant tumor and closely related to intestinal microbiome disorders. Especially, Fusobacterium nucleatum (F. nucleatum) is one of the most prevalent pathogens in CRC. However, its change in CRC patients of Northwest China, an area with a high incidence of gastrointestinal tumors, is unclear, and therapeutic strategies targeting F. nucleatum remain unresolved. Here, fecal samples of healthy people and CRC patients were studied using 16S rRNA sequencing to explore microbial community alterations. Additionally, vanillin derivate (IPM711 and IPM712) intervention by coculture with CRC cells and potential mechanism were investigated. Results showed that intestinal microbial homeostasis was gradually dysregulated, and the abundance of Fusobacterium was higher in CRC patients. Moreover, IPM711 and IPM712 showed better anti-F. nucleatum activity than vanillin by increasing cell membrane permeability and destroying bacterial integrity. In addition, IPM711 and IPM712 could downregulate the expression of E-cadherin and β-catenin, thus, suppressing the migration of HCT116. Collectively, IPM711 and IPM712 have both anticolorectal cancer and anti-F. nucleatum activities, providing potential natural product drug candidates for microbe-targeted strategies for the treatment of CRC.

Highlights

Colorectal cancer (CRC) is the third most prevalent cancer in both sexes combined, with an incidence of 6.1% and mortality of 9.2% (Bray et al, 2018)
Gut microbiome dysbiosis and increase in Fusobacterium are common in CRC patients and verified in our sample set in Northwest China for the first time
Disorders of the gut microbiome have been acknowledged as one important factor of CRC development, and panels of different microbes can be used as biomarkers for early diagnosis

Summary

Introduction

Colorectal cancer (CRC) is the third most prevalent cancer in both sexes combined, with an incidence of 6.1% and mortality of 9.2% (Bray et al, 2018). Infectious agent, and oncogenic microorganism, F. nucleatum was reported to be more enriched in CRC tissues of patients with recurrence and strongly associated with shorter recurrence-free survival (RFS) (Yu et al, 2017). It can promote colorectal carcinogenesis, exhibiting increased virulence in CRC when compared with the normal tissues (Rubinstein et al, 2013). F. nucleatum adheres to and invades CRC cells via its unique FadA adhesin, binding to E-cadherin and forming FadA–E-cadherin–Annexin A1-β-catenin complex in cancerous cells It can induce oncogenic and inflammatory responses (Rubinstein et al, 2013). Changes in gut microbiome, especially F. nucleatum in CRC patients in Northwest China, are rarely studied, which is an area with higher incidence of gastrointestinal tumors

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