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METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification

Background: Osteosarcoma (OS) is the most prevalent bone cancer among children and adolescents, with relatively high mortality rates. RNA N6-methyladenosine (m6A) is the most common human mRNA modification with diverse functions in a variety of biological processes. Previous studies indicated that m...

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Autores principales: Zhou, Xinying, Yang, Yang, Li, Yuejun, Liang, Guojun, Kang, Dawei, Zhou, Bing, Li, Qingchu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8790117/
https://www.ncbi.nlm.nih.gov/pubmed/35096816
http://dx.doi.org/10.3389/fcell.2021.784719
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author Zhou, Xinying
Yang, Yang
Li, Yuejun
Liang, Guojun
Kang, Dawei
Zhou, Bing
Li, Qingchu
author_facet Zhou, Xinying
Yang, Yang
Li, Yuejun
Liang, Guojun
Kang, Dawei
Zhou, Bing
Li, Qingchu
author_sort Zhou, Xinying
collection PubMed
description Background: Osteosarcoma (OS) is the most prevalent bone cancer among children and adolescents, with relatively high mortality rates. RNA N6-methyladenosine (m6A) is the most common human mRNA modification with diverse functions in a variety of biological processes. Previous studies indicated that methyltransferase-like 3 (METTL3), the first methyltransferase to be identified, acted as an oncogene or tumor suppressor in multiple human cancers. However, its functions and underlying mechanisms in OS progression remain unclear; therefore, we explored these processes. Methods: We used real-time quantitative PCR (RT-qPCR) and Western blot assays to explore METTL3 expression in OS tumor tissues and five OS cell lines to assess its clinical significance. To further examine the functional role of METTL3 during OS progression, CCK-8 analyses, transwell assays, and xenograft model studies were conducted after silencing METTL3. Additionally, underlying mechanisms were also explored using RIP-seq and RIP-qPCR approaches. Results: METTL3 was upregulated in OS tumor tissues and cell lines and was associated with a worse prognosis. Moreover, METTL3 silencing suppressed OS cell proliferation, migration, and invasion. Also, in vivo METTL3 oncogenic functions were confirmed in the xenograft model. Comprehensive mechanistic analyses identified long non-coding RNA (lncRNA) DANCR as a potential target of METTL3, as indicated by reduced DANCR levels after METTL3 silencing. Also, lncRNA DANCR knockdown repressed OS cell proliferation, migration, and invasion. Furthermore, both METTL3 and lncRNA DANCR silencing significantly suppressed OS growth and metastasis. Finally, we hypothesized that METTL3 regulated DANCR expression via m6A modification-mediated DANCR mRNA stability. Conclusion: METTL3 contributes to OS progression by increasing DANCR mRNA stability via m6A modification, meaning that METTL3 may be a promising therapeutic target for OS treatment.
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spelling pubmed-87901172022-01-27 METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification Zhou, Xinying Yang, Yang Li, Yuejun Liang, Guojun Kang, Dawei Zhou, Bing Li, Qingchu Front Cell Dev Biol Cell and Developmental Biology Background: Osteosarcoma (OS) is the most prevalent bone cancer among children and adolescents, with relatively high mortality rates. RNA N6-methyladenosine (m6A) is the most common human mRNA modification with diverse functions in a variety of biological processes. Previous studies indicated that methyltransferase-like 3 (METTL3), the first methyltransferase to be identified, acted as an oncogene or tumor suppressor in multiple human cancers. However, its functions and underlying mechanisms in OS progression remain unclear; therefore, we explored these processes. Methods: We used real-time quantitative PCR (RT-qPCR) and Western blot assays to explore METTL3 expression in OS tumor tissues and five OS cell lines to assess its clinical significance. To further examine the functional role of METTL3 during OS progression, CCK-8 analyses, transwell assays, and xenograft model studies were conducted after silencing METTL3. Additionally, underlying mechanisms were also explored using RIP-seq and RIP-qPCR approaches. Results: METTL3 was upregulated in OS tumor tissues and cell lines and was associated with a worse prognosis. Moreover, METTL3 silencing suppressed OS cell proliferation, migration, and invasion. Also, in vivo METTL3 oncogenic functions were confirmed in the xenograft model. Comprehensive mechanistic analyses identified long non-coding RNA (lncRNA) DANCR as a potential target of METTL3, as indicated by reduced DANCR levels after METTL3 silencing. Also, lncRNA DANCR knockdown repressed OS cell proliferation, migration, and invasion. Furthermore, both METTL3 and lncRNA DANCR silencing significantly suppressed OS growth and metastasis. Finally, we hypothesized that METTL3 regulated DANCR expression via m6A modification-mediated DANCR mRNA stability. Conclusion: METTL3 contributes to OS progression by increasing DANCR mRNA stability via m6A modification, meaning that METTL3 may be a promising therapeutic target for OS treatment. Frontiers Media S.A. 2022-01-12 /pmc/articles/PMC8790117/ /pubmed/35096816 http://dx.doi.org/10.3389/fcell.2021.784719 Text en Copyright © 2022 Zhou, Yang, Li, Liang, Kang, Zhou and Li. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Zhou, Xinying
Yang, Yang
Li, Yuejun
Liang, Guojun
Kang, Dawei
Zhou, Bing
Li, Qingchu
METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification
title METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification
title_full METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification
title_fullStr METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification
title_full_unstemmed METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification
title_short METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification
title_sort mettl3 contributes to osteosarcoma progression by increasing dancr mrna stability via m6a modification
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8790117/
https://www.ncbi.nlm.nih.gov/pubmed/35096816
http://dx.doi.org/10.3389/fcell.2021.784719
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