YTHDF2 exerts tumor-suppressor roles in gastric cancer via up-regulating PPP2CA independently of m <sup>6</sup>A modification

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Abstract

Background

YTHDF2 is one of important readers of N6-methyladenosine (m ⁶A) modification on RNA. Growing evidence implicates that YTHDF2 takes an indispensable part in the regulation of tumorigenesis and metastasis in different cancers, but its biological functions and underlying mechanisms remain elusive in gastric cancer (GC).

Aim

To investigate the clinical relevance and biological function of YTHDF2 in GC.

Results

Compared with matched normal stomach tissues, YTHDF2 expression was markedly decreased in gastric cancer tissues. The expression level of YTHDF2 was inversely associated with gastric cancer patients’ tumor size, AJCC classification and prognosis. Functionally, YTHDF2 reduction facilitated gastric cancer cell growth and migration in vitro and in vivo, whereas YTHDF2 overexpression exhibited opposite phenotypes. Mechanistically, YTHDF2 enhanced expression of PPP2CA, the catalytic subunit of PP2A (Protein phosphatase 2A), in an m ⁶A-independent manner, and silencing of PPP2CA antagonized the anti-tumor effects caused by overexpression of YTHDF2 in GC cells.

Conclusion

These findings demonstrate that YTHDF2 is down-regulated in GC and its down-regulation promotes GC progression via a possible mechanism involving PPP2CA expression, suggesting that YTHDF2 may be a hopeful biomarker for diagnosis and an unrevealed treatment target for GC.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12575-023-00195-1.

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Most cited references 36

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Cancer statistics in China, 2015.

Wanqing Chen, Rongshou Zheng, Peter D Baade … (2016)

With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. Because of China's massive population (1.37 billion), previous national incidence and mortality estimates have been limited to small samples of the population using data from the 1990s or based on a specific year. With high-quality data from an additional number of population-based registries now available through the National Central Cancer Registry of China, the authors analyzed data from 72 local, population-based cancer registries (2009-2011), representing 6.5% of the population, to estimate the number of new cases and cancer deaths for 2015. Data from 22 registries were used for trend analyses (2000-2011). The results indicated that an estimated 4292,000 new cancer cases and 2814,000 cancer deaths would occur in China in 2015, with lung cancer being the most common incident cancer and the leading cause of cancer death. Stomach, esophageal, and liver cancers were also commonly diagnosed and were identified as leading causes of cancer death. Residents of rural areas had significantly higher age-standardized (Segi population) incidence and mortality rates for all cancers combined than urban residents (213.6 per 100,000 vs 191.5 per 100,000 for incidence; 149.0 per 100,000 vs 109.5 per 100,000 for mortality, respectively). For all cancers combined, the incidence rates were stable during 2000 through 2011 for males (+0.2% per year; P = .1), whereas they increased significantly (+2.2% per year; P < .05) among females. In contrast, the mortality rates since 2006 have decreased significantly for both males (-1.4% per year; P < .05) and females (-1.1% per year; P < .05). Many of the estimated cancer cases and deaths can be prevented through reducing the prevalence of risk factors, while increasing the effectiveness of clinical care delivery, particularly for those living in rural areas and in disadvantaged populations.

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N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

Guifang Jia, Ye Fu, Xu Zhao … (2011)

We report here that FTO (fat mass and obesity-associated protein) exhibits efficient oxidative demethylation activity of abundant N 6-methyladenosine (m6A) residues in RNA in vitro. FTO knockdown with siRNA led to an increased level of m6A in mRNA, whereas overexpression of FTO resulted in a decreased level of m6A in human cells. We further show that FTO partially colocalizes with nuclear speckles, supporting m6A in nuclear RNA as a physiological substrate of FTO.

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Author and article information

Contributors

Yandong Li: yandongli2009@gmail.com

Yong Gao: drgaoyong@tongji.edu.cn

Journal

Journal ID (nlm-ta): Biol Proced Online

Journal ID (iso-abbrev): Biol Proced Online

Title: Biological Procedures Online

Publisher: BioMed Central (London )

ISSN (Electronic): 1480-9222

Publication date (Electronic): 4 March 2023

Publication date PMC-release: 4 March 2023

Publication date Collection: 2023

Volume: 25

Electronic Location Identifier: 6

Affiliations

[1 ]GRID grid.452753.2, ISNI 0000 0004 1799 2798, Department of Oncology, , Shanghai East Hospital, School of Medicine, Tongji University, ; 150 Ji-Mo Rd., Shanghai, 200120 China

[2 ]GRID grid.452753.2, ISNI 0000 0004 1799 2798, Department of Oncology, , Shanghai East Hospital Ji’an Hospital, ; Ji’an City, 343000 Jiangxi Province China

[3 ]GRID grid.24516.34, ISNI 0000000123704535, School of Medicine, , Tongji University, ; Shanghai, 200120 China

Article

Publisher ID: 195

DOI: 10.1186/s12575-023-00195-1

PMC ID: 9985201

PubMed ID: 36870954

SO-VID: 26b14d49-a6b6-4bae-9a48-2559fac13cd1

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 26 October 2022

Date accepted : 24 February 2023

Funding

Funded by: National Natural Science Foundation of China

Award ID: 82160468

Award ID: 81972290

Funded by: the Top-level Clinical Discipline Project of Shanghai Pudong

Award ID: PWYgf2021-07

Funded by: Shanghai Municipal Science and Technology Innovation Action Plan in Clinical Medical Field

Award ID: 19411951100

Custom metadata

ScienceOpen disciplines: Life sciences

Keywords: ythdf2,gastric cancer,progression,ppp2ca

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: ythdf2, gastric cancer, progression, ppp2ca

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