دورية أكاديمية
METTL14-mediated epitranscriptome modification of MN1 mRNA promote tumorigenicity and all-trans-retinoic acid resistance in osteosarcoma.
| العنوان: | METTL14-mediated epitranscriptome modification of MN1 mRNA promote tumorigenicity and all-trans-retinoic acid resistance in osteosarcoma. |
|---|---|
| المؤلفون: | Li HB; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China., Huang G; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China., Tu J; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China., Lv DM; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China., Jin QL; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China., Chen JK; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China., Zou YT; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China., Lee DF; Department of Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX 77030-1501, US., Shen JN; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. Electronic address: shenjn@mail.sysu.edu.cn., Xie XB; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. Electronic address: xiexbiao@mail.sysu.edu.cn. |
| المصدر: | EBioMedicine [EBioMedicine] 2022 Aug; Vol. 82, pp. 104142. Date of Electronic Publication: 2022 Jul 07. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101647039 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-3964 (Electronic) Linking ISSN: 23523964 NLM ISO Abbreviation: EBioMedicine Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Amsterdam] : Elsevier B.V., [2014]- |
| مواضيع طبية MeSH: | Bone Neoplasms*/genetics , Osteosarcoma*/drug therapy , Osteosarcoma*/genetics, Adolescent ; Cell Line, Tumor ; Chromatography, Liquid ; Humans ; Methyltransferases ; RNA ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins ; Tandem Mass Spectrometry ; Trans-Activators/metabolism ; Tretinoin/metabolism ; Tretinoin/pharmacology ; Tumor Suppressor Proteins/metabolism |
| مستخلص: | Background: Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents. The molecular mechanism behind OS progression and metastasis remains poorly understood, which limits the effectiveness of current therapies. RNA N 6 -methyladenosine (m 6 A) modification plays a critical role in influencing RNA fate. However, the biological significance of m 6 A modification and its potential regulatory mechanisms in the development of OS remain unclear. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS), dot blotting, and colorimetric ELISA were used to detect m 6 A levels. Western blotting, quantitative real-time PCR (RT-qPCR) and immunohistochemistry (IHC) were used to investigate METTL14 expression levels. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL14. RNA pull-down and RNA immunoprecipitation (RIP) assays were conducted to explore the specific binding of target genes and relevant m 6 A "readers". RNA stability and polysome analysis assays were used to detect the half-lives and translation efficiencies of the downstream genes of METTL14. IHC and clinical data were applied to explore the clinical correlations of METTL14 and its downstream target genes with the prognosis of OS. Findings: We observed the abundance of m 6 A modifications in OS and revealed that METTL14 plays an oncogenic role in facilitating OS progression. MeRIP-seq and RNA-seq revealed that MN1 is a downstream gene of METTL14. MN1 contributes to tumor progression and all-trans-retinoic acid (ATRA) chemotherapy resistance in OS. Mechanistically, MN1 is methylated by METTL14, specifically in the coding sequence (CDS) regions, and this modification is recognized by the specific m 6 A reader insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) to prevent MN1 mRNA degradation and promote it translation efficiency. IHC showed that MN1 expression was positively correlated with METTL14 and IGF2BP2 expression in OS tissues. The METTL14-IGF2BP2-MN1 panel demonstrated more promising prognostic value for OS patients than any of these molecules individually. Interpretation: Our study revealed that METTL14 contributes to OS progression and ATRA resistance as an m 6 A RNA methylase by regulating the stability and translation efficiency of MN1 and thus provides both an underlying biomarker panel for prognosis prediction in OS patients. Funding: This work was supported by the National Natural Science Foundation of China (Grants 81972510 and 81772864). Competing Interests: Declaration of interests No potential conflicts of interest were disclosed. (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Lung metastasis; METTL14; Osteosarcoma; m(6)A modification |
| المشرفين على المادة: | 0 (IGF2BP2 protein, human) 0 (MN1 protein, human) 0 (RNA, Messenger) 0 (RNA-Binding Proteins) 0 (Trans-Activators) 0 (Tumor Suppressor Proteins) 5688UTC01R (Tretinoin) 63231-63-0 (RNA) EC 2.1.1.- (METTL14 protein, human) EC 2.1.1.- (Methyltransferases) |
| تواريخ الأحداث: | Date Created: 20220710 Date Completed: 20220816 Latest Revision: 20220819 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC9272358 |
| DOI: | 10.1016/j.ebiom.2022.104142 |
| PMID: | 35810559 |
| قاعدة البيانات: | MEDLINE |
Full Text via ClinicalKey 
Full Text Finder | تدمد: | 2352-3964 |
|---|---|
| DOI: | 10.1016/j.ebiom.2022.104142 |