Fusobacterium nucleatum upregulates MMP7 to promote metastasis-related characteristics of colorectal cancer cell via activating MAPK(JNK)-AP1 axis

Suwen Ou; Haipeng Chen; Hufei Wang; Jinhua Ye; Huidi Liu; Yangbao Tao; Songlin Ran; Xiaoqin Mu; Fangzhou Liu; Shuang Zhu; Kangjia Luo; Zilong Guan; Yinghu Jin; Rui Huang; Yanni Song; Shu-Lin Liu

doi:10.1186/s12967-023-04527-3

Fusobacterium nucleatum upregulates MMP7 to promote metastasis-related characteristics of colorectal cancer cell via activating MAPK(JNK)-AP1 axis

J Transl Med. 2023 Oct 9;21(1):704. doi: 10.1186/s12967-023-04527-3.

Authors

Suwen Ou^#^{1

2}, Haipeng Chen^#³, Hufei Wang^#¹, Jinhua Ye^#¹, Huidi Liu^{4

5}, Yangbao Tao¹, Songlin Ran¹, Xiaoqin Mu^{4

5}, Fangzhou Liu¹, Shuang Zhu¹, Kangjia Luo^{1

6}, Zilong Guan^{1

7}, Yinghu Jin¹, Rui Huang⁸, Yanni Song⁹, Shu-Lin Liu^{10

11

12}

Affiliations

¹ Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China.
² Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
³ Department of Colorectal Surgery, National Clinical Research Center of Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
⁴ Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
⁵ Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University-University of Calgary, Harbin Medical University, Harbin, 150081, China.
⁶ Department of Gastrointestinal Surgery, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, 315020, China.
⁷ Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150000, China.
⁸ Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China. huangrui2019@163.com.
⁹ Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China. yannimd@126.com.
¹⁰ Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. slliu@hrbmu.edu.cn.
¹¹ Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University-University of Calgary, Harbin Medical University, Harbin, 150081, China. slliu@hrbmu.edu.cn.
¹² Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, T2N 4N1, Canada. slliu@hrbmu.edu.cn.

^# Contributed equally.

Abstract

Background: Colorectal cancer (CRC) is the third most common malignant tumor. Fusobacterium nucleatum (F. nucleatum) is overabundant in CRC and associated with metastasis, but the role of F. nucleatum in CRC cell migration and metastasis has not been fully elucidated.

Methods: Differential gene analysis, protein-protein interaction, robust rank aggregation analysis, functional enrichment analysis, and gene set variation analysis were used to figure out the potential vital genes and biological functions affected by F. nucleatum infection. The 16S rDNA sequencing and q-PCR were used to detect the abundance of F. nucleatum in tissues and stools. Then, we assessed the effect of F. nucleatum on CRC cell migration by wound healing and transwell assays, and confirmed the role of Matrix metalloproteinase 7 (MMP7) induced by F. nucleatum in cell migration. Furthermore, we dissected the mechanisms involved in F. nucleatum induced MMP7 expression. We also investigated the MMP7 expression in clinical samples and its correlation with prognosis in CRC patients. Finally, we screened out potential small molecular drugs that targeted MMP7 using the HERB database and molecular docking.

Results: F. nucleatum infection altered the gene expression profile and affected immune response, inflammation, biosynthesis, metabolism, adhesion and motility related biological functions in CRC. F. nucleatum was enriched in CRC and promoted the migration of CRC cell by upregulating MMP7 in vitro. MMP7 expression induced by F. nucleatum infection was mediated by the MAPK(JNK)-AP1 axis. MMP7 was highly expressed in CRC and correlated with CMS4 and poor clinical prognosis. Small molecular drugs such as δ-tocotrienol, 3,4-benzopyrene, tea polyphenols, and gallic catechin served as potential targeted therapeutic drugs for F. nucleatum induced MMP7 in CRC.

Conclusions: Our study showed that F. nucleatum promoted metastasis-related characteristics of CRC cell by upregulating MMP7 via MAPK(JNK)-AP1 axis. F. nucleatum and MMP7 may serve as potential therapeutic targets for repressing CRC advance and metastasis.

Keywords: Colorectal cancer; Fusobacterium nucleatum; Matrix metalloproteinase 7; Migration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms* / pathology
Fusobacterium Infections* / complications
Fusobacterium Infections* / diagnosis
Fusobacterium Infections* / microbiology
Fusobacterium nucleatum / genetics
Humans
Matrix Metalloproteinase 7 / genetics
Molecular Docking Simulation

Substances

Matrix Metalloproteinase 7
MMP7 protein, human