Excessive miR-25-3p maturation via N 6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression

Nat Commun. 2019 Apr 23;10(1):1858. doi: 10.1038/s41467-019-09712-x.

Abstract

N6-methyladenosine (m6A) 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 m6A 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 m6A modification promotes the development and progression of pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Pancreatic Ductal / blood
  • Carcinoma, Pancreatic Ductal / etiology
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Co-Repressor Proteins / metabolism
  • DNA Methylation
  • Disease Progression
  • Epithelial Cells / pathology
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Male
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • MicroRNAs / blood
  • MicroRNAs / metabolism*
  • Middle Aged
  • Nuclear Proteins / metabolism
  • Pancreatic Ducts / cytology
  • Pancreatic Ducts / pathology
  • Pancreatic Neoplasms / blood
  • Pancreatic Neoplasms / etiology
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology*
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA-Binding Proteins / metabolism
  • Repressor Proteins
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Smoke / adverse effects*
  • Smoking / adverse effects
  • Smoking / blood
  • Tobacco / toxicity*
  • Up-Regulation

Substances

  • Co-Repressor Proteins
  • DGCR8 protein, human
  • MIRN25 microRNA, human
  • MicroRNAs
  • NKAP protein, human
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Repressor Proteins
  • Smoke
  • N-methyladenosine
  • Methyltransferases
  • METTL3 protein, human
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • PHLPP2 protein, human
  • Phosphoprotein Phosphatases
  • Adenosine