Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression

Abstract

N 6 -methyladenosine (m 6 A) modification is an important mechanism in miRNA processing and maturation, but the role of its aberrant regulation in human diseases remained unclear. Here, we demonstrate that oncogenic primary microRNA-25 (miR-25) in pancreatic duct epithelial cells can be excessively maturated by cigarette smoke condensate (CSC) via enhanced m 6 A modification that is mediated by NF-κB associated protein (NKAP). This modification is catalyzed by overexpressed methyltransferase-like 3 (METTL3) due to hypomethylation of the METTL3 promoter also caused by CSC. Mature miR-25, miR-25-3p, suppresses PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2), resulting in the activation of oncogenic AKT-p70S6K signaling, which provokes malignant phenotypes of pancreatic cancer cells. High levels of miR-25-3p are detected in smokers and in pancreatic cancers tissues that are correlated with poor prognosis of pancreatic cancer patients. These results collectively indicate that cigarette smoke-induced miR-25-3p excessive maturation via m 6 A modification promotes the development and progression of pancreatic cancer.

The interplay between m6A RNA methylation and noncoding RNA in cancer

“…Another study revealed the role of m6A in miRNA processing, and the role of miR-25-3p was recently reported. In this study, Zang indicated the effect of cigarette smoking on m6A-modified miR-25-3p maturation in pancreatic ductal adenocarcinoma [76]. This research showed that the specific regulatory mechanism of METTL3 upregulation caused by cigarette smoking involves the epigenetic regulation of the METTL3 promoter.…”

“…In this case, as a protein molecule, DGCR8 has potential as a therapeutic target. Another study reported that the upregulation of METTL3 caused an increase in miR-25-3p and that miR-25-3p could promote the expression of its target protein PHLPP2 to promote pancreatic ductal adenocarcinoma occurrence [76]. Similar to DGCR8, the protein PHLPP2 also shows potential for use in targeted therapy.…”

METTL3 regulates inflammatory pain by modulating m 6 A‐dependent pri‐miR‐365‐3p processing

“…In this study, our results support this. 32 Due to the strong connection between DNA methylation and pain processes, 33 we therefore proposed that DNA methylation might be an important mechanism by which METTL3 expression is regulated by pain. To our knowledge, this is the first study on METTL3-mediated m 6 A modification in miRNA processing in pain research.…”

Functions of N6-methyladenosine and its role in cancer

“…Cigarette smoke condensate promotes m6A, thus contributing to maturation of oncogene miR-25-3p in pancreatic tumor. MiR-25-3p inhibits PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2), leading to the activation of oncogenic AKT-p70S6K signaling [135].…”