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Cellular and Molecular Biology

METTL14-mediated N6-methyladenosine modification of Pten mRNA inhibits tumour progression in clear-cell renal cell carcinoma

British Journal of Cancer volume 127, pages 30–42 (2022)Cite this article

Subjects

Abstract

Background

Clear-cell renal-cell carcinoma (ccRCC) is one of the leading causes of tumour-related death worldwide. Methyltransferase-like 14 (METTL14) is reported to regulate m6A modification in cancers. The aim of this study is to investigate the biological function and molecular mechanism of METTL14 in the pathogenesis of ccRCC.

Methods

Quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were used to detect the expression of METTL14 and Pten. METTL14 overexpression or knockdown was used in the in vitro and in vivo studies to investigate the biological functions of METTL14. m6A-RNA immunoprecipitation and RNA immunoprecipitation were used to investigate the m6A modification mediated by METTL14.

Results

METTL14 expression was significantly down-regulated in ccRCC tissues. Functionally, upregulation of METTL14 inhibited ccRCC cells proliferation and migration in vitro. METTL14 overexpression significantly inhibited the activation of the phosphoinositide 3 kinase (PI3K)/AKT signalling pathway. Furthermore, phosphate and tension homology deleted on chromosome ten (Pten) is a target of METTL14. Overexpression of METTL14 increased the m6A enrichment of Pten, and promoted Pten expression. METTL14-enhanced Pten mRNA stability was dependent on YTHDF1.

Conclusions

METTL14-mediated m6A modification of Pten mRNA inhibited tumour progression, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for ccRCC.

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Fig. 1: METTL14 is low expressed in the ccRCC and correlates with poor prognosis.
Fig. 2: METTL14 level is upregulated in ccRCC.
Fig. 3: METTL14 inhibits ccRCC cell proliferation and migration in vitro.
Fig. 4: Downregulation of METTL14 promotes the AKT signalling activation.
Fig. 5: BEZ235 abrogates the effect of METTL14 knockdown in vitro.
Fig. 6: METTL14 overexpression enhances Pten mRNA stability via an m6A-YTHDF1-dependent manner.
Fig. 7: METTL14 inhibits ccRCC cell proliferation, migration and the AKT signalling activation via an m6A-YTHDF1-dependent manner.
Fig. 8: METTL14 inhibits ccRCC cell proliferation, migration and the AKT signalling activation through upregulating Pten in vitro.
Fig. 9: Pten reverses the effect of METTL14 knockdown in vivo.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Funding

The study was supported by the National Natural Science Foundation of China (31560327 and 31560325). We would like to thank all the researchers and study participants for their contributions.

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Authors and Affiliations

  1. Department of Laboratory Medicine, The Affiliated Hospital of Zunyi Medical University, 563003, Zunyi, P. R. China

    Lili Zhang & Sen Qiao

  2. School of Laboratory Medicine, Zunyi Medical University, 563003, Zunyi, P. R. China

    Lili Zhang, Xiaofang Luo & Sen Qiao

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All authors contributed to this review with conception and design, literature review, drafting and critical revision, editing and approval of the final version.

Corresponding author

Correspondence to Sen Qiao.

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The consent agreement was signed and approved by the Ethics Committee of The Affiliated Hospital of Zunyi Medical University. All patients involved in the present study didn’t receive chemotherapy or radiotherapy before the surgery.

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Zhang, L., Luo, X. & Qiao, S. METTL14-mediated N6-methyladenosine modification of Pten mRNA inhibits tumour progression in clear-cell renal cell carcinoma. Br J Cancer 127, 30–42 (2022). https://doi.org/10.1038/s41416-022-01757-y

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