PLAA suppresses ovarian cancer metastasis via METTL3-mediated m <sup>6</sup>A modification of TRPC3 mRNA

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Abstract

Wide metastasis contributes to a high death rate in ovarian cancer, and understanding of the molecular mechanism helps to find effective targets for metastatic ovarian cancer therapy. It has been found that phospholipase A2-activating protein (PLAA) is inactivated in some cancers, but its role in cancer metastasis remains unknown. Here, we found that PLAA was significantly downregulated in ovarian cancer highly metastatic cell lines and patients, and the low expression of PLAA was associated with poorer prognosis and high-risk clinicopathological features of patients. PLAA inhibited the migration and invasion of ovarian cancer cells and metastasis of transplanted tumor in the orthotopic xenograft mouse model. Meanwhile, PLAA inhibited metastasis of ovarian cancer by inhibiting transient receptor potential channel canonical 3 (TRPC3)-mediated the intracellular Ca ²⁺ level. Mechanistically, PLAA inhibited methyltransferase-like 3 (METTL3) expression through the ubiquitin-mediated degradation, and METTL3 stabilized TRPC3 mRNA expression via N6-methyladenosine (m ⁶A) modification. Our study verified the function and mechanism of the PLAA-METTL3-TRPC3 axis involved in ovarian cancer metastasis, with a view to providing a potential therapeutic approach for ovarian cancer.

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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. Incidence data (through 2017) 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 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.

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Author and article information

Contributors

Weiguo Lu:

ORCID: http://orcid.org/0000-0003-2062-7145

lbwg@zju.edu.cn

Journal

Journal ID (nlm-ta): Oncogene

Journal ID (iso-abbrev): Oncogene

Title: Oncogene

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0950-9232

ISSN (Electronic): 1476-5594

Publication date (Electronic): 22 July 2022

Publication date PMC-release: 22 July 2022

Publication date (Print): 2022

Volume: 41

Issue: 35

Pages: 4145-4158

Affiliations

[1 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Women’s Reproductive Health Laboratory of Zhejiang Province, Women’s Hospital, , Zhejiang University School of Medicine, ; Hangzhou, 310006 Zhejiang China

[2 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Gynecologic Oncology, Women’s Hospital, , Zhejiang University School of Medicine, ; Hangzhou, 310006 Zhejiang China

[3 ]GRID grid.414252.4, ISNI 0000 0004 1761 8894, Department of Obstetrics and Gynecology, the Seventh Medical Centre, , Chinese PLA General Hospital, ; Beijing, 100853 China

[4 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Cancer Center, , Zhejiang University, ; Hangzhou, 310058 Zhejiang China

[5 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Obstetrics and Gynecology, The First Affiliated Hospital, , Zhejiang University School of Medicine, ; Hangzhou, 310003 Zhejiang China

[6 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, , Zhejiang University School of Medicine, ; Hangzhou, 310006 Zhejiang China

Author information

Weiguo Lu http://orcid.org/0000-0003-2062-7145

Article

Publisher ID: 2411

DOI: 10.1038/s41388-022-02411-w

PMC ID: 9418004

PubMed ID: 35869392

SO-VID: 2e0d9189-893b-4958-89df-4f0b32ede887

License:

Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 4 April 2022

Date revision received : 1 July 2022

Date accepted : 7 July 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82072856

Award Recipient : Zhangjin Shen Lingkai Gu Yuwan Liu Lingfang Wang Jiawei Zhu Xinyi Wei Jiaying Wang Songfa Zhang Xiaodong Cheng Xing Xie Weiguo Lu

Funded by: FundRef https://doi.org/10.13039/501100008990, Science and Technology Department of Zhejiang Province;

Award ID: 2019C03010

Award Recipient : Zhangjin Shen Lingkai Gu Lingfang Wang Jiawei Zhu Sangsang Tang Xinyi Wei Jiaying Wang Songfa Zhang Xinyu Wang Xiaodong Cheng Xing Xie Weiguo Lu

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: ovarian cancer,cell migration,epigenetics

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: ovarian cancer, cell migration, epigenetics

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