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Fusobacterium nucleatum Potentiates Intestinal Tumorigenesis in Mice via a Toll-Like Receptor 4/p21-Activated Kinase 1 Cascade

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Abstract

Background

The underlying pathogenic mechanism of Fusobacterium nucleatum in the carcinogenesis of colorectal cancer has been poorly understood.

Methods

Using C57BL/6-ApcMin/+ mice, we investigated gut microbial structures with F. nucleatum, antibiotics, and Toll-like receptor 4 (TLR4) antagonist TAK-242 treatment. In addition, we measured intestinal tumor formation and the expression of TLR4, p21-activated kinase 1 (PAK1), phosphorylated-PAK1 (p-PAK1), phosphorylated-β-catenin S675 (p-β-catenin S675), and cyclin D1 in mice with different treatments.

Results

Fusobacterium nucleatum and antibiotics treatment altered gut microbial structures in mice. In addition, F. nucleatum invaded into the intestinal mucosa in large amounts but were less abundant in the feces of F. nucleatum-fed mice. The average number and size of intestinal tumors in F. nucleatum groups was significantly increased compared to control groups in ApcMin/+ mice (P < 0.05). The expression of TLR4, PAK1, p-PAK1, p-β-catenin S675, and cyclin D1 was significantly increased in F. nucleatum groups compared to the control groups (P < 0.05). Moreover, TAK-242 significantly decreased the average number and size of intestinal tumors compared to F. nucleatum groups (P < 0.05). The expression of p-PAK1, p-β-catenin S675, and cyclin D1 was also significantly decreased in the TAK-242-treated group compared to F. nucleatum groups (P < 0.05).

Conclusions

Fusobacterium nucleatum potentiates intestinal tumorigenesis in ApcMin/+ mice via a TLR4/p-PAK1/p-β-catenin S675 cascade. Fusobacterium nucleatum-induced intestinal tumorigenesis can be inhibited by TAK-242, implicating TLR4 as a potential target for the prevention and therapy of F. nucleatum-related colorectal cancer.

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Acknowledgments

This work was supported by Grants from Natural Science Foundation of the Sichuan Science and Technology Agency (No. 201665).

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Author notes

  1. Yaxin Wu and Jiao Wu have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China

    Yaxin Wu, Jiao Wu, Ting Chen, Qing Li, Wei Peng, Huan Li, Xiaowei Tang & Xiangsheng Fu

  2. Endoscopy Center, The Affiliated Hospital of Southwest Medical University, Street Taiping 25#, Luzhou, 646000, Sichuan, China

    Yaxin Wu, Jiao Wu, Ting Chen, Qing Li, Wei Peng, Huan Li & Xiangsheng Fu

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  1. Yaxin Wu
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  2. Jiao Wu
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  4. Qing Li
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  5. Wei Peng
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Correspondence to Xiangsheng Fu.

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Wu, Y., Wu, J., Chen, T. et al. Fusobacterium nucleatum Potentiates Intestinal Tumorigenesis in Mice via a Toll-Like Receptor 4/p21-Activated Kinase 1 Cascade. Dig Dis Sci 63, 1210–1218 (2018). https://doi.org/10.1007/s10620-018-4999-2

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  • DOI: https://doi.org/10.1007/s10620-018-4999-2

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