METTL3-mediated m <sup>6</sup>A modification of lncRNA SNHG3 accelerates gastric cancer progression by modulating miR-186-5p/cyclinD2 axis

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Abstract

Objectives

METTL3 as an m ⁶A methyltransferase acts in diverse malignancies including gastric cancer (GC). We aimed to reveal the underlying mechanisms by which METTL3 contributes to gastric carcinogenesis.

Methods

The association of METTL3 and SNHG3 with GC was analyzed by qRT-PCR, Western blot, and TCGA cohort. The functional experiments were implemented to uncover the role of METTL3 in GC. m ⁶A dot blot and MeRIP were used to determine METTL3-mediated m ⁶A modification of lncRNA SNHG3. The effect of METTL3 on SNHG3-mediated miR-186-5p/cyclinD2 axis was evaluated by luciferase gene report, RT-qPCR, and Western blot assays.

Results

We found that METTL3 was remarkably elevated in GC tissues and correlated with poor survival in patients with GC. Silencing of METTL3 impaired GC cell growth and invasion, whereas restored METTL3 expression promoted these effects. Mechanistically, reduced expression of METTL3 decreased SNHG3 m ⁶A level and caused a decrease in SNHG3 expression, which could further act as a sponge of miR-186-5p to upregulate cyclinD2. Overexpression of SNHG3 attenuated METTL3 knockdown-induced anti-proliferating and miR-186-5p upregulation and cyclinD2 downregulation.

Conclusion

We find that METTL3-mediated m ⁶A modification of lncRNA SNHG3 accelerates GC progression by modulating miR-186-5p/cyclinD2 axis.

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Most cited references 42

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Cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.

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Visualizing and interpreting cancer genomics data via the Xena platform

Mary Goldman, Brian Craft, Mim Hastie … (2020)

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Is Open Access

The role of m 6 A RNA methylation in human cancer

Xiao-Yu Chen, Jing Zhang, Jin-Shui Zhu (2019)

N6-methyladenosine (m6A) is identified as the most common, abundant and conserved internal transcriptional modification, especially within eukaryotic messenger RNAs (mRNAs). M6A modification is installed by the m6A methyltransferases (METTL3/14, WTAP, RBM15/15B and KIAA1429, termed as “writers”), reverted by the demethylases (FTO and ALKBH5, termed as “erasers”) and recognized by m6A binding proteins (YTHDF1/2/3, IGF2BP1 and HNRNPA2B1, termed as “readers”). Acumulating evidence shows that, m6A RNA methylation has an outsize effect on RNA production/metabolism and participates in the pathogenesis of multiple diseases including cancers. Until now, the molecular mechanisms underlying m6A RNA methylation in various tumors have not been comprehensively clarified. In this review, we mainly summarize the recent advances in biological function of m6A modifications in human cancer and discuss the potential therapeutic strategies.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Immunopathol Pharmacol

Journal ID (iso-abbrev): Int J Immunopathol Pharmacol

Journal ID (hwp): spiji

Journal ID (publisher-id): IJI

Title: International Journal of Immunopathology and Pharmacology

Publisher: SAGE Publications (Sage UK: London, England )

ISSN (Print): 0394-6320

ISSN (Electronic): 2058-7384

Publication date (Electronic): 12 October 2023

Publication date Collection: Jan-Dec 2023

Volume: 37

Electronic Location Identifier: 03946320231204694

Affiliations

[1-03946320231204694]Department of Pathology, Tongji University School of Medicine, Ringgold 278245, universityShanghai Tenth People’s Hospital; , Shanghai, China

Author notes

[*]Hao Xi, Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, No. 301 Yanchang Middle Road, Shanghai 200072, China. Email: shiyuanxihao@ 123456163.com

[*]

Guo Ji and Xiu Wang contributed equally to the present work.

Author information

Hao Xi https://orcid.org/0000-0002-1667-6203

Article

Publisher ID: 10.1177_03946320231204694

DOI: 10.1177/03946320231204694

PMC ID: 10571673

PubMed ID: 37823387

SO-VID: d98acf23-05a2-4f95-af25-4a98d80f2cd8

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 18 February 2023

Date accepted : 14 September 2023

Funding

Funded by: Shanghai Natural Science Foundation;

Award ID: 21ZR1448700

Custom metadata

typesetter ts10

cover-date January-December 2023

Keywords: m6a,mettl3,snhg3,mir-186,gastric cancer,growth

Data availability:

Keywords: m6a, mettl3, snhg3, mir-186, gastric cancer, growth