NamiRNA-enhancer network of miR-492 activates the NR2C1-TGF-β/Smad3 pathway to promote epithelial-mesenchymal transition of pancreatic cancer

Carcinogenesis. 2023 May 26;44(2):153-165. doi: 10.1093/carcin/bgac102.

Abstract

Pancreatic cancer (PaCa) is one of the most fatal malignancies of the digestive system, and most patients are diagnosed at advanced stages due to the lack of specific and effective tumor-related biomarkers for the early detection of PaCa. miR-492 has been found to be upregulated in PaCa tumor tissue and may serve as a potential therapeutic target. However, the molecular mechanisms by which miR-492 promotes PaCa tumor growth and progression are unclear. In this study, we first found that miR-492 in enhancer loci activated neighboring genes (NR2C1/NDUFA12/TMCC3) and promoted PaCa cell proliferation, migration, and invasion in vitro. We also observed that miR-492-activating genes significantly enriched the TGF-β/Smad3 signaling pathway in PaCa to promote epithelial-mesenchymal transition (EMT) during tumorigenesis and development. Using CRISPR-Cas9 and ChIP assays, we further observed that miR-492 acted as an enhancer trigger, and that antagomiR-492 repressed PaCa tumorigenesis in vivo, decreased the expression levels of serum TGF-β, and suppressed the EMT process by downregulating the expression of NR2C1. Our results demonstrate that miR-492, as an enhancer trigger, facilitates PaCa progression via the NR2C1-TGF-β/Smad3 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs* / genetics
  • NADPH Dehydrogenase / genetics
  • NADPH Dehydrogenase / metabolism
  • Pancreatic Neoplasms* / genetics
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Transforming Growth Factor beta
  • MicroRNAs
  • SMAD3 protein, human
  • Smad3 Protein
  • NDUFA12 protein, human
  • NADPH Dehydrogenase
  • MIRN492 microRNA, human