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METTL3 facilitates colorectal cancer growth through altering the abundance of intestinal Akkermansia muciniphila

Cancer Gene Therapy volume 32, pages 1098–1106 (2025)Cite this article

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Abstract

Colorectal cancer (CRC) is a prevalent malignant tumor that poses a significant threat to human health; however, the precise mechanism underlying its onset remains elusive. In this study, we utilized metagenomic sequencing to reveal the dysregulation of intestinal microbiota caused by CRC. Single-cell sequencing data showed elevated mRNA expression of methyltransferase-like protein 3 (METTL3) in CRC, which was correlated with the abundance of intestinal microbiota. Furthermore, we found that METTL3 promotion of CRC progression is microbiota-dependent. Using induced METTL3fl/fl Vil1-cre+/− mice, we identified the microbiota regulated by METTL3 in CRC. Our research indicates that METTL3 leads to high expression of HIF1α, which promotes the expression of lipocalin 2 (LCN2) in CRC cells, inhibiting the abundance of Akkermansia muciniphila, thereby promoting CRC progression.

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Fig. 1: CRC significantly altered the composition of the mouse fecal microbiota.
Fig. 2: METTL3 inhibitor STM2457 inhibits mouse CRC progression with a partial dependence on intestinal microbiota.
Fig. 3: Intestinal METTL3 deficiency altered bacterial abundance in the CRC mouse fecal microbiota.
Fig. 4: Intestinal METTL3 deficiency upregulated Akk abundance in the CRC mouse fecal microbiota.
Fig. 5: METTL3-HIF1α-LCN2 signaling axis inhibits Akk abundance.
Fig. 6: Addition of Akk potentiates the anti-tumor efficacy of the METTL3 inhibitor STM2457 in a pseudo-germ-free CRC mouse model.

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Data availability

The data that support the findings of this study are available in NCBI Sequence Read Archive (SRA) under the accession number PRJNA1270767 and can be accessed via the following links: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1270767.

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Funding

National Natural Science Foundation of China (82203607), China Postdoctoral Science Foundation (2022M721540), Guangdong Basic and Applied Basic Research Foundation (2021A1515111186 and 2021B1515120001) and Guangzhou Basic and Applied Basic Research Foundation (2024A04J6605).

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Author notes

  1. These authors contributed equally: Ling Wu, Weidong Lian, Rui Bai.

Authors and Affiliations

  1. Department of Pathology, The Eighth Affiliated Hospital, Southern Medical University (The First People’s Hospital of Shunde, Foshan), Foshan, China

    Ling Wu, Hao Chen & Liang Zhao

  2. Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Ling Wu, Rui Bai, Hao Chen, Jianghua Wu & Liang Zhao

  3. Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Weidong Lian

  4. Department of Pathology, The First Affiliated Hospital of Xinxiang University, Xinxiang, China

    Hanyu Li

Authors
  1. Ling Wu
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  4. Hao Chen
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Contributions

LZ led the study design and prepared the manuscript. LW, W-DL, and RB carried out the experiments. HC performed statistical analysis. J-HW and H-YL assisted in tissue sample collection and data analysis.

Corresponding author

Correspondence to Liang Zhao.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Shunde Hospital, Southern Medical University, and the ethical approval permit number is KYLS20221126. All experiments involving patients complied with the Declaration of Helsinki. Informed consent was obtained from all participants. All animal experiments were approved by the Institutional Animal Care and Use Committee of Shunde Hospital, Southern Medical University (IACUC permit NYBY-WL-2505-001). Experimental mice were maintained in a specific pathogen-free facility in accordance with approved protocols.

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Wu, L., Lian, W., Bai, R. et al. METTL3 facilitates colorectal cancer growth through altering the abundance of intestinal Akkermansia muciniphila. Cancer Gene Ther 32, 1098–1106 (2025). https://doi.org/10.1038/s41417-025-00949-x

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