Metformin Inhibits the Progression of Pancreatic Cancer Through Regulating miR-378a-3p/VEGFA/RGC-32 Axis

Cancer Med. 2024 Dec;13(23):e70446. doi: 10.1002/cam4.70446.

Abstract

Background: Pancreatic cancer (PC) is a major contributor to global cancer-related mortality. While the inhibitory effect of metformin (Met) on PC has been reported, the underlying mechanism remains elusive.

Methods: We established BxPC-3 cell models with miR-378a-3p and VEGFA knockdown. The expression of miR-378a-3p, VEGFA, and RGC-32 in PC and normal tissues was analyzed using GEPIA, TCGA databases. Cell proliferation, invasion, migration, and apoptosis were assessed through CCK8, Transwell, wound healing, and flow cytometry.

Results: Significantly lower expression of miR-378a-3p was observed in PC tissues and cells. Knockdown of miR-378a-3p reversed the impact of Met on cell viability in PANC-1 and BxPC3. VEGFA emerged as a potential regulator in PC and a downstream target of miR-378a-3p. The interaction between VEGFA and RGC-32 played a crucial role in PC regulation. Knockdown of VEGFA substantially reversed the impact of miR-378a-3p inhibitor on tumor growth and the epithelial-mesenchymal transition (EMT) process. Moreover, knockdown of VEGFA effectively countered the influence of miR-378a-3p inhibitor on cell viability and the EMT process in BxPC3 cells.

Conclusions: Met exerted inhibitory effects on PC through the miR-378a-3p/VEGFA/RGC-32 pathway. Strategies targeting the miR-378a-3p/VEGFA/RGC-32 axis represent a novel avenue for the prevention and treatment of PC.

Keywords: Met; VEGFA; miR‐378a‐3p; pancreatic cancer.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation* / drug effects
  • Disease Progression
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Metformin* / pharmacology
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / pathology
  • Vascular Endothelial Growth Factor A* / genetics
  • Vascular Endothelial Growth Factor A* / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • MicroRNAs
  • MIRN378 microRNA, human
  • Vascular Endothelial Growth Factor A
  • Metformin
  • VEGFA protein, human
  • Nerve Tissue Proteins
  • Muscle Proteins