Knock down of BMSC-derived Wnt3a or its antagonist analogs attenuate colorectal carcinogenesis induced by chronic Fusobacterium nucleatum infection.

Abstract

By establishing the Fusobacterium nucleatum (F. nucleatum) infected-bone mesenchymal stem cells (BMSCs) transplantation model in APCMin/+ mice, we investigated the role of BMSCs in the development of intestinal tumors induced by F. nucleatum. ApcMin/++F. nucleatum + BMSCs mice showed increased susceptibility to intestinal tumors and accelerated tumor growth. BMSCs could also enhance tumor-initiating capability, invasive traits after F. nucleatum infection in vitro, and tumorigenicity in a nude murine model. Mechanistically, BMSCs were recruited to the submucosa, migrated to the mucosal layer, and might activate the canonical Wnt/β-catenin/TGIF axis signaling. Further mechanistic results illustrated increased production of the Wnt3a protein was found in ApcMin/++F. nucleatum + BMSCs mice, and BMSCs were likely the major source of Wnt3a. Intriguingly, a deletion of Wnt3a via BMSC interference or antagonist analogs led to a significantly attenuated capacity of ApcMin/++F. nucleatum mice to generate intestinal tumors. The findings suggest that BMSCs have the potential to migrate and accelerate F. nucleatum-induced colorectal tumorigenesis by modulating Wnt3a secretion; knockdown of BMSC-derived Wnt3a or antagonist analogs could attenuate carcinogenesis. Thus, Wnt3a might be a potential pharmaceutical target for the prevention and treatment of F. nucleatum-related colorectal cancer.

• Authors: Rong Lin, Chaoqun Han, Zhen Ding, Huiying Shi, Ruohang He, Jun Liu, Wei Qian, Qin Zhang, Xiaochao Fu, Xiaohua Deng, Shunchang Zhou, Xiaohua Hou
• Journal: Cancer letters (Cancer Lett) Vol. 495 Pg. 165-179 (12 28 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 32920199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• WNT3A protein, human
• Wnt3A Protein

Topics

• Animals
• Caco-2 Cells
• Cell Line, Tumor
• Colorectal Neoplasms (microbiology, therapy)
• Female
• Fusobacterium Infections (complications, genetics, therapy)
• Fusobacterium nucleatum (pathogenicity)
• Gene Knockdown Techniques
• HT29 Cells
• Humans
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (cytology, metabolism)
• Mice
• Wnt Signaling Pathway
• Wnt3A Protein (genetics, metabolism)
• Xenograft Model Antitumor Assays