METTL3/ <i>MALAT1</i>/ELAVL1 Axis Promotes Tumor Growth in Ovarian Cancer

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Abstract

Background

Studies increasingly recognize the role of N6-methyladenosine ( m6A) modification in cancer occurrence and development. METTL3 is a core catalytic subunit of m6A-modified methyltransferases complex, but its regulatory mechanism in ovarian cancer (OC) is not clear.

Methods

In this study, GEPIA 2.0 database was applied for expression analysis, survival analysis and correlation analysis for OC. Additionally, in vitro and in vivo assays were conducted to explore regulatory mechanisms of METTL3 in OC.

Results

We found that METTL3 and MALAT1 were significantly overexpressed in OC tissues and cells compared to normal ovarian tissues and cells. The proliferation rate of OC cells was reduced significantly after knocking down the expression of METTL3 or MALAT1. Subsequently, MALAT1 as oncogene was found to interact with METTL3 and was upregulated in OC tissues and cells. Silencing MALAT1 inhibited OC cell proliferation. Further studies indicated that METTL3 enhanced the stability of MALAT1 by promoting the m6A modification of MALAT1 and that ELAVL1 as a downstream binding protein significantly up-regulated MALAT1 expression.

Conclusion

In conclusion, METTL3 was a carcinogenic molecule that promoted the occurrence of OC. The potential mechanism of the carcinogenic effect of METTL3 was realized by enhancing the m6A modification of MALAT1 mRNA through RNA binding protein ELAVL1.

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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, 2022

Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2022)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) 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 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.

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Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons.

Kate D Meyer, Yogesh Saletore, Paul Zumbo … (2012)

Methylation of the N(6) position of adenosine (m(6)A) is a posttranscriptional modification of RNA with poorly understood prevalence and physiological relevance. The recent discovery that FTO, an obesity risk gene, encodes an m(6)A demethylase implicates m(6)A as an important regulator of physiological processes. Here, we present a method for transcriptome-wide m(6)A localization, which combines m(6)A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-Seq). We use this method to identify mRNAs of 7,676 mammalian genes that contain m(6)A, indicating that m(6)A is a common base modification of mRNA. The m(6)A modification exhibits tissue-specific regulation and is markedly increased throughout brain development. We find that m(6)A sites are enriched near stop codons and in 3' UTRs, and we uncover an association between m(6)A residues and microRNA-binding sites within 3' UTRs. These findings provide a resource for identifying transcripts that are substrates for adenosine methylation and reveal insights into the epigenetic regulation of the mammalian transcriptome. Copyright © 2012 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Onco Targets Ther

Journal ID (iso-abbrev): Onco Targets Ther

Journal ID (publisher-id): ott

Title: OncoTargets and Therapy

Publisher: Dove

ISSN (Electronic): 1178-6930

Publication date (Electronic): 08 February 2024

Publication date Collection: 2024

Volume: 17

Pages: 85-97

Affiliations

[1 ]Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University , Guangzhou, Guangdong, People’s Republic of China

[2 ]Department of Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University , Guangzhou, Guangdong, People’s Republic of China

Author notes

Correspondence: Kefei Gao; Rui Zhao, Department of Obstetrics and Gynaecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University , 9 Jinsui Road, Tianhe District, Guangzhou, Guangdong, 510623, People’s Republic of China, Email gaokefei2020@yeah.net; zhaorui_fezx@163.com

[*]

These authors contributed equally to this work

Article

Publisher ID: 431810

DOI: 10.2147/OTT.S431810

PMC ID: 10860502

PubMed ID: 38348427

SO-VID: 6cc11890-e3ea-4274-99ee-8fbb73c1dc56

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 25 August 2023

Date accepted : 24 January 2024

Page count

Figures: 5, References: 36, Pages: 13

Funding

Funded by: study was funded by the Research foundation of Guangzhou Women and Children’s Medical Center for Clinical Doctor;

Funded by: Science and Technology Program of Guangzhou, China;

This study was funded by the Research foundation of Guangzhou Women and Children’s Medical Center for Clinical Doctor (2021BS044, 2020RC004), and the Science and Technology Program of Guangzhou, China (2024A03J0807, 2024A03J0956).

METTL3/ MALAT1/ELAVL1 Axis Promotes Tumor Growth in Ovarian Cancer

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Abstract

Background

Methods

Results

Conclusion

Related collections

Karger: Oncology

Most cited references 36

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

Cancer statistics, 2022

Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons.

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