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MiR-103-3p targets the m⁶ A methyltransferase METTL14 to inhibit osteoblastic bone formation.

ABSTRACT: Impaired osteoblast function is involved in osteoporosis, and microRNA (miRNA) dysregulation may cause abnormal osteoblast osteogenic activity. However, the influence of miRNA on osteoblast activity and the underlying mechanisms remain elusive. In this study, miR-103-3p was found to be negatively correlated with bone formation in bone specimens from elderly women with fractures and ovariectomized (OVX) mice. Additionally, miR-103-3p directly targeted Mettl14 to inhibit osteoblast activity, and METTL14-dependent N⁶ -methyladenosine (m⁶ A) methylation inhibited miR-103-3p processing by the microprocessor protein DGCR8 and promoted osteoblast activity. Moreover, miR-103-3p inhibited bone formation in vivo, and therapeutic inhibition of miR-103-3p counteracted the decreased bone formation in OVX mice. Further, METTL14 was negatively correlated with miR-103-3p but positively correlated with bone formation in bone specimens from elderly women with fractures and OVX mice. Collectively, our results highlight the critical roles of the miR-103-3p/METTL14/m⁶ A signaling axis in osteoblast activity, identifying this axis as a potential target for ameliorating osteoporosis.

SUBMITTER: Sun Z

PROVIDER: S-EPMC7884043 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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MiR-103-3p targets the m<sup>6</sup> A methyltransferase METTL14 to inhibit osteoblastic bone formation.

Sun Zhongyang Z Wang Han H Wang Yuxiang Y Yuan Guodong G Yu Xin X Jiang Hui H Wu Qi Q Yang Binkui B Hu Zebing Z Shi Fei F Cao Xinsheng X Zhang Shu S Guo Ting T Zhao Jianning J

Aging cell 20210113 2

Impaired osteoblast function is involved in osteoporosis, and microRNA (miRNA) dysregulation may cause abnormal osteoblast osteogenic activity. However, the influence of miRNA on osteoblast activity and the underlying mechanisms remain elusive. In this study, miR-103-3p was found to be negatively correlated with bone formation in bone specimens from elderly women with fractures and ovariectomized (OVX) mice. Additionally, miR-103-3p directly targeted Mettl14 to inhibit osteoblast activity, and M ...[more]

PMID: 33440070

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Project description:BackgroundN6-methyladenosine (m6A) RNA methylation and circular RNAs (circRNAs) have been shown to act vital roles in multiple malignancies including gastric cancer (GC). However, there is little knowledge about how m6A modification of circRNAs contributes to GC progression.MethodsThe association of METTL14 expression with the clinicopathological characteristics and prognosis in patients with GC was assessed by Western blot, Immunohistochemistry and public datasets. In vitro and vivo function experiments were conducted to investigate the role of METTL14 in GC. Furthermore, m6A-circRNA epitranscriptomic microarray was utilized to identify METTL14-mediated m6A modification of circRNAs, which were validated by methylated RNA immunoprecipitation (Me-RIP), RT-qPCR and rescue experiments in GC cells. The sponge of circORC5 with miR-30c-2-3p was confirmed by luciferase gene report and RNA immunoprecipitation assays. The expression, localization and prognosis of circORC5 in GC were evaluated by fluorescence in situ hybridization. The effects of METTL14 and (or) circORC5 on miR-30c-2-3p-mediated AKT1S1 and EIF4B were estimated by RT-qPCR and Western blot analyses.ResultsWe found that METTL14 was downregulated in GC tissue samples and its low expression acted as a prognostic factor of poor survival in patients with GC. Ectopic expression of METTL14 markedly repressed growth and invasion of GC cells in vitro and in vivo, whereas knockdown of METTL14 harbored the opposite effects. Mechanically, m6A-circRNA epitranscriptomic microarray and Me-RIP identified circORC5 as the downstream target of METTL14. Silencing of METTL14 reduced the m6A level of circORC5, but increased circORC5 expression. Moreover, circORC5 could sponge miR-30c-2-3p, and reverse METTL14-caused upregulation of miR-30c-2-3p and downregulation of AKT1S1 and EIF4B. In addition, circORC5 possessed a negative correlation with miR-30c-2-3p and indicated a poor survival in GC.ConclusionOur findings demonstrate that METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.

Dataset Information

MiR-103-3p targets the m⁶ A methyltransferase METTL14 to inhibit osteoblastic bone formation.

Publications

MiR-103-3p targets the m<sup>6</sup> A methyltransferase METTL14 to inhibit osteoblastic bone formation.

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Dataset Information

MiR-103-3p targets the m6 A methyltransferase METTL14 to inhibit osteoblastic bone formation.

Publications

MiR-103-3p targets the m<sup>6</sup> A methyltransferase METTL14 to inhibit osteoblastic bone formation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

MiR-103-3p targets the m⁶ A methyltransferase METTL14 to inhibit osteoblastic bone formation.