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      METTL3 Accelerates Breast Cancer Progression via Regulating EZH2 m 6A Modification

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          Abstract

          We aimed to investigate the bio-functions of METTL3 in promoting breast cancer (BCa) progression via regulating N6-methyladenosine (m 6A) modification of EZH2 mRNA. METTL3 levels in 48 cases of BCa and matched paracancerous tissues were detected. In the meantime, METTL3 in BCa patients with different staging or lymphatic metastasis states were examined. Prognosis of the BCa patients was analyzed using Kaplan–Meier estimator. Protein levels of EMT-associated genes and invasive and migratory abilities were evaluated. The binding relationship between EZH2 and METTL3 was analyzed via RIP. Besides, m 6A modification of EZH2 mRNA was explored. E-Cadherin level in MCF-7 cells with EZH2 knockdown was tested. Subsequently, ChIP was done to verify the interaction between E-cadherin and EZH2. Regulatory effects of METTL3/E-cadherin axis on EMT and metastasis of BCa were finally determined. METTL3 was upregulated in BCa tissues compared to paracancerous ones. METTL3 was especially higher in T3-T4 BCa or those with lymphatic metastasis. BCa patients expressing high level of METTL3 experienced worse survival. METTL3 was identically upregulated in BCa cell lines. Knockdown of METTL3 in MCF-7 cells attenuated EMT and metastatic abilities. Protein level of EZH2 was downregulated after knockdown of METTL3 in MCF-7 cells, while its mRNA level was not influenced by METTL3. Furthermore, METTL3 was confirmed to interact with EZH2, and m 6A modification existed in EZH2 mRNA. Knockdown of EZH2 greatly upregulated mRNA level of E-cadherin, and later, ChIP assay confirmed the interaction between EZH2 and E-cadherin. E-Cadherin could abolish the effects of METTL3 on BCa metastasis and epithelial-mesenchymal transition. METTL3 is upregulated in BCa. It could regulate the protein level of EZH2 through m 6A modification to promote EMT and metastasis in BCa cells, thereafter aggravating the progression of BCa.

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          Most cited references36

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase

            The methyltransferase like 3 (METTL3)-containing methyltransferase complex catalyzes the N6-methyladenosine (m6A) formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms' tumor 1-associating protein (WTAP) and methyltransferase like 14 (METTL14). WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic activity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
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              Cancer metastasis: building a framework.

              Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenvironment that is distant from the primary tumor. This process involves both the selection of traits that are advantageous to cancer cells and the concomitant recruitment of traits in the tumor stroma that accommodate invasion by metastatic cells. Recent conceptual and technological advances promote our understanding of the origins and nature of cancer metastasis.
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                Author and article information

                Contributors
                Journal
                J Healthc Eng
                J Healthc Eng
                JHE
                Journal of Healthcare Engineering
                Hindawi
                2040-2295
                2040-2309
                2022
                29 March 2022
                : 2022
                : 5794422
                Affiliations
                1Department of Oncological Surgery, First Affiliated Hospital of Jiamusi University, Jiamusi, China
                2Department of Pathology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
                3Department of General Surgery, The First Hospital of Qiqihar, Qiqihar, China
                4Department of General Surgery, Affiliated Qiqihar Hospital, Southern Medical University, Qiqihar, China
                Author notes

                Academic Editor: Deepak Kumar Jain

                Author information
                https://orcid.org/0000-0002-1160-0373
                Article
                10.1155/2022/5794422
                8983232
                35392146
                4caa70ba-6ccd-457d-9b33-255fb7defbfc
                Copyright © 2022 Shaojun Hu et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 January 2022
                : 4 February 2022
                : 10 February 2022
                Categories
                Research Article

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