METTL3 contributes to slow transit constipation by regulating miR‐30b‐5p/PIK3R2/Akt/mTOR signaling cascade through DGCR8

Abstract

Background N6‐methyladenosine (m6A) is the most prevalent methylation modification of eukaryotic RNA, and methyltransferase‐like 3 (METTL3) plays a vital role in multiple cell functions. This study aimed to investigate the role of m6A methylase METTL3 in slow transit constipation (STC). Material and Method The expression of METTL3 and DGCR8 was measured in STC tissues and glutamic acid‐induced interstitial cells of Cajal (ICCs). The effects of METTL3, miR‐30b‐5p, and DGCR8 on the biological characteristics of ICCs were investigated on the basis of loss‐of‐function analyses. Luciferase reporter assay was used to identify the direct binding sites of miR‐30b‐5p with PIK3R2. Results The results showed that the METTL3, DGCR8, miR‐30b‐5p, and the methylation level of m6A were significantly increased in STC tissues and glutamic acid‐induced ICCs. Silencing of METTL3 and miR‐30b‐5p inhibited apoptosis, autophagy, and pyroptosis of glutamic acid‐induced ICCs. Moreover, overexpression of miR‐30b‐5p reversed the cytoprotection of METTL3 knockdown in glutamic acid‐induced ICCs. Besides, DGCR8 knockdown could facilitate cell growth and decrease apoptotic glutamic acid‐induced ICCs. Mechanically, we illustrated that METTL3 in glutamic acid‐induced ICCs significantly accelerated the maturation of pri‐miR‐30b‐5p by m6A methylation modification, resulting in the reduction of PIK3R2, which results in the inhibition of PI3K/Akt/mTOR pathway and ultimately leads to the cell death of STC. Conclusions Collectively, these data demonstrated that METTL3 promoted the apoptosis, autophagy, and pyroptosis of glutamic acid‐induced ICCs by interacting with the DGCR8 and successively modulating the miR‐30b‐5p/PIK3R2 axis in an m6A‐dependent manner, and METTL3 may be a potential therapeutic target for STC.

METTL3 promotes hyperoxia-induced pyroptosis in neonatal bronchopulmonary dysplasia by inhibiting ATG8-mediated autophagy

“…Previous studies have shown that METTL3 regulates pyroptosis by regulating autophagy. [21] Whether METTL3 regulates the pyroptosis of BEAS-2B cells by inhibiting autophagy. In vivo assays showed that hyperoxia decreased the protein expression of ATG8 and LC3II/I but increased p62, which was abrogated by METTL3 deficiency ( Fig.…”

A novel pyroptosis-associated lncRNA LINC01133 promotes pancreatic adenocarcinoma development via miR-30b-5p/SIRT1 axis

“…In PAAD, miR-30b-5p promotes angiogenesis by downregulating GJA1 expression [ 49 ]. In addition, miR-30b-5p promotes cell pyroptosis via the PIK3R2/Akt/mTOR pathway in glutamic acid-induced interstitial cells [ 50 ]. However, little is known about the role of miR-30b-5p in PAAD cells.…”

Preliminary study based on methylation and transcriptome gene sequencing of lncRNAs and immune infiltration in hypopharyngeal carcinoma

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