Dataset Information

METTL3 promotes IL-1?-induced degeneration of endplate chondrocytes by driving m6A-dependent maturation of miR-126-5p.

ABSTRACT: METTL3 is an important regulatory molecule in the process of RNA biosynthesis. It mainly regulates mRNA translation, alternative splicing and microRNA maturation by mediating m6A-dependent methylation. Interleukin 1? (IL-1?) is an important inducer of cartilage degeneration that can induce an inflammatory cascade reaction in chondrocytes and inhibit the normal biological function of cells. However, it is unclear whether IL-1? is related to METTL3 expression or plays a regulatory role in endplate cartilage degeneration. In this study, we found that the expression level of METTL3 and methylation level of m6A in human endplate cartilage with different degrees of degeneration were significantly different, indicating that the methylation modification of m6A mediated by METTL3 was closely related to the degeneration of human endplate cartilage. Next, through a series of functional experiments, we found that miR-126-5p can play a significant role in IL-1?-induced degeneration of endplate chondrocytes. Moreover, we found that miR-126-5p can inhibit the PI3K/Akt signalling pathway by targeting PIK3R2 gene, leading to the disorder of cell vitality and functional metabolism. To further determine whether METTL3 could regulate miR-126-5p maturation, we first confirmed that METTL3 can bind the key protein underlying pri-miRNA processing, DGCR8. Additionally, when METTL3 expression was inhibited, the miR-126-5p maturation process was blocked. Therefore, we hypothesized that METTL3 can promote cleavage of pri-miR-126-5p and form mature miR-126-5p by combining with DGCR8.

SUBMITTER: Xiao L

PROVIDER: S-EPMC7754036 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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METTL3 promotes IL-1β-induced degeneration of endplate chondrocytes by driving m6A-dependent maturation of miR-126-5p.

Xiao Liang L Zhao Quanlai Q Hu Bo B Wang Jing J Liu Chen C Xu Hongguang H

Journal of cellular and molecular medicine 20201023 23

METTL3 is an important regulatory molecule in the process of RNA biosynthesis. It mainly regulates mRNA translation, alternative splicing and microRNA maturation by mediating m6A-dependent methylation. Interleukin 1β (IL-1β) is an important inducer of cartilage degeneration that can induce an inflammatory cascade reaction in chondrocytes and inhibit the normal biological function of cells. However, it is unclear whether IL-1β is related to METTL3 expression or plays a regulatory role in endplate ...[more]

PMID: 33098220

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Project description:BackgroundMETTL3 is known to be involved in all stages in the life cycle of RNA. It affects the tumor formation by the regulation the m6A modification in the mRNAs of critical oncogenes or tumor suppressors. In bladder cancer, METTL3 could promote the bladder cancer progression via AFF4/NF-κB/MYC signaling network by an m6A dependent manner. Recently, METTL3 was also found to affect the m6A modification in non-coding RNAs including miRNAs, lincRNAs and circRNAs. However, whether this mechanism is related to the proliferation of tumors induced by METTL3 is not reported yet.MethodsQuantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of METTL3 in bladder cancer. The survival analysis was adopted to explore the association between METTL3 expression and the prognosis of bladder cancer. Bladder cancer cells were stably transfected with lentivirus and cell proliferation and cell cycle, as well as tumorigenesis in nude mice were performed to assess the effect of METTL3 in bladder cancer. RNA immunoprecipitation (RIP), co-immunoprecipitations and RNA m6A dot blot assays were conducted to confirm that METTL3 interacted with the microprocessor protein DGCR8 and modulated the pri-miR221/222 process in an m6A-dependent manner. Luciferase reporter assay was employed to identify the direct binding sites of miR221/222 with PTEN. Colony formation assay and CCK8 assays were conducted to confirm the function of miR-221/222 in METTL3-induced cell growth in bladder cancer.ResultsWe confirmed the oncogenic role of METTL3 in bladder cancer by accelerating the maturation of pri-miR221/222, resulting in the reduction of PTEN, which ultimately leads to the proliferation of bladder cancer. Moreover, we found that METTL3 was significantly increased in bladder cancer and correlated with poor prognosis of bladder cancer patients.ConclusionsOur findings suggested that METTL3 may have an oncogenic role in bladder cancer through interacting with the microprocessor protein DGCR8 and positively modulating the pri-miR221/222 process in an m6A-dependent manner. To our knowledge, this is the first comprehensive study that METTL3 affected the tumor formation by the regulation the m6A modification in non-coding RNAs, which might provide fresh insights into bladder cancer therapy.

Dataset Information

METTL3 promotes IL-1?-induced degeneration of endplate chondrocytes by driving m6A-dependent maturation of miR-126-5p.

Publications

METTL3 promotes IL-1β-induced degeneration of endplate chondrocytes by driving m6A-dependent maturation of miR-126-5p.

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