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Translational Therapeutics

Novel evidence for m6A methylation regulators as prognostic biomarkers and FTO as a potential therapeutic target in gastric cancer

Abstract

Background

While emerging evidence indicates that N6-methyladenosine (m6A) regulators play crucial roles in cancer progression, their clinical significance in gastric cancer (GC) has thus far not been elucidated.

Methods

We investigated the expression of the m6A regulator genes and their prognostic potential in a large clinical cohort of 173 GC patients using qRT-PCR assays. In addition, we undertook a series of in-vitro and in-vivo functional studies to investigate the oncogenic role of FTO.

Results

GC patients with low expression of METTL3, METTL14, ALKBH5, WTAP and YTHDF1 demonstrated significantly poor OS, while patients with high FTO expression exhibited markedly worse OS. Furthermore, the cumulative risk-score derived from these gene panel also significantly associated with poor OS, with a corresponding hazard ratio of 5.47 (95% CI: 3.18–9.41, p < 0.0001). We observed that FTO expression was frequently upregulated in GC cell lines, with epithelial-mesenchymal-transition (EMT) features. FTO knockdown in HGC27 and AGS cells inhibited cell proliferation and migratory potential, while its overexpression in MKN28 cells resulted in enhanced proliferation and migration. Finally, confirming our in-vitro findings, FTO suppression led to significant tumour growth inhibition in a HGC27 xenograft model.

Conclusions

We demonstrate that m6A regulators may serve as promising prognostic biomarkers in GC. Our functional studies reveal that FTO is an important oncogene and may be a promising therapeutic target associated with EMT-alterations in gastric cancer.

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Fig. 1: Prognostic significance of the five gene m6A classifier in GC patients.
Fig. 2: Stable knockdown of FTO suppressed cell proliferation and migration in gastric cancer cells.
Fig. 3: FTO inhibitor (MA2) suppressed oncogenic role and overexpression of FTO enhanced the tumour progression in GC cell lines.
Fig. 4: Stable knockdown of FTO and inhibition by MA2 resulted in tumour growth inhibition in HGC27 xenografts.
Fig. 5: FTO inhibition resulted in the modulation of core of epithelial-mesenchymal-transition related genes in GC cell lines.

Data availability

All data are available within the article.

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Acknowledgements

We would like to acknowledge Preethi Ravindranathan, Aki Sakatani, Michael Hsieh, and Kinnari Pankaj Modi for experimental advice, and acknowledge Divya Pasham, Ashley Cao, Maddie Brown, and Anna Wakita for experimental support.

Funding

This work was supported by CA184792, CA187956, CA227602, CA072851 and CA202797, grants from the National Cancer Institute, National Institutes of Health, and a pilot grant from the Stupid Strong Foundation to A Goel.

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Concept and design: TS, RK and AG; Acquisition, analysis, or interpretation of data: TS, RK; Drafting of the manuscript: TS, RK, YO, MO, YT and AG; Statistical analysis: TS, and RK; Administrative, technical, or material support: TS, YO, MO, YT and AG; Supervision: AG

Corresponding author

Correspondence to Ajay Goel.

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Shimura, T., Kandimalla, R., Okugawa, Y. et al. Novel evidence for m6A methylation regulators as prognostic biomarkers and FTO as a potential therapeutic target in gastric cancer. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01581-w

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