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Demethylase FTO enhances the PI3K/Akt signaling to promote gastric cancer malignancy

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Abstract

Enhanced expression of fat mass and obesity-associated protein (FTO) has been reported in gastric cancer (GC). Bioinformatical studies indicate that FTO expression is correlated with the patients’ overall survival (OS). How FTO exerts its promotion effects on GC development and affects OS remains largely unknown. In this study, the prognostic relevance of FTO expression in human GC tissues and the molecular mechanisms underlying FTO’s promotion roles were investigated. Kaplan–Meier survival curve analysis revealed that the patients with high FTO levels had shorter OS compared to those with low FTO expression (p < 0.0001). Univariate and multivariate COX regression analyses showed that the patients’ OS was affected by FTO status (p < 0.0001, p = 0.001, respectively). FTO knockdown in HGC27 cells by shRNAs reduced cell proliferation, colony formation, migration and invasion, while FTO overexpression in AGS cells had reverse effects. FTO knockdown in HGC27 cells also suppressed the tumor growth in a mouse xenograft model. High-throughput transcriptome sequencing indicated that FTO enhanced the PI3K/Akt signaling, which was confirmed in vitro. In summary, our research revealed that FTO is a potent prognostic biomarker of GC. FTO enhances the PI3K/Akt signaling and thus, promotes GC development.

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Data availability

Data supporting the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

CI:

Confidence interval

EMT:

Epithelial-mesenchymal transition

FTO:

Fat mass and obesity-associated protein

GC:

Gastric cancer

HR:

Hazard ratio

IHC:

Immunohistochemistry

m6A:

N6-methyladenosine

OS:

Overall survival

SD:

Standard deviation

TCGA:

The Cancer Genome Atlas

TNM:

Tumor node metastasis

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Acknowledgements

Gratitude should be expressed to the Comprehensive Experiment Center and the Department of Immunology, School of Basic Medical Sciences, Anhui Medical University for giving precious help in this paper.

Funding

This study was supported by the grants from The National Natural Science Youth Foundation of China (No. 8190102788).

Author information

Authors and Affiliations

  1. Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230031, Anhui, China

    Yuxuan Zhu & Zheng Fang

  2. Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230031, Anhui, China

    Jing Yang, Yongxiang Li & Zheng Fang

  3. Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, 230032, Anhui, China

    Jiegou Xu

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  1. Yuxuan Zhu
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Contributions

All authors contributed to the study conception and design. ZF conceived and designed the study and experiments involved. YZ performed the experiments and analyzed the data. YL provided gastric cancer samples. JY made suggestions on bioinformatics analysis. YZ and JX wrote the manuscript. All authors read, commented and approved the final manuscript.

Corresponding authors

Correspondence to Yongxiang Li, Jiegou Xu or Zheng Fang.

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Competing interests

The authors disclose no potential conflicts of interest.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Anhui Medical University (20190362). All animal experiments in this study were approved by the Animal Ethics Committee of Anhui Medical University (LLSC20190402).

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Zhu, Y., Yang, J., Li, Y. et al. Demethylase FTO enhances the PI3K/Akt signaling to promote gastric cancer malignancy. Med Oncol 40, 130 (2023). https://doi.org/10.1007/s12032-023-01990-2

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