Macrophage-derived Exosomal microRNA-501-3p Promotes Progression of Pancreatic Ductal Adenocarcinoma Through the TGFBR3-mediated TGF-β Signaling Pathway

J Exp Clin Cancer Res. 2019 Jul 15;38(1):310. doi: 10.1186/s13046-019-1313-x.

Abstract

Background: Exosomes from cancer cells or immune cells, carrying bio-macromolecules or microRNAs (miRNAs), participate in tumor pathogenesis and progression by modulating microenvironment. Our study aims to investigate the role of these microRNA-501-3p (miR-501-3p) containing exosomes derived from tumor-associated macrophage (TAM) in the progression of pancreatic ductal adenocarcinoma (PDAC).

Methods: Firstly, the function of TAM recruitment in PDAC tissues was assessed, followed by identification of the effects of M2 macrophage-derived exosomes on PDAC cell activities and tumor formation and metastasis in mice. In silico analysis was conducted to predict differentially expressed genes and regulatory miRNAs related to PDAC treated with macrophages, which determined miR-501-3p and TGFBR3 for subsequent experiments. Next, gain- and loss-of-function experiments were performed to examine their role in PDAC progression with the involvement of the TGF-β signaling pathway.

Results: TAM recruitment in PDAC tissues was associated with metastasis. Highly expressed miR-501-3p was observed in PDAC tissues and TAM-derived exosomes. Both M2 macrophage-derived exosomes and miR-501-3p promoted PDAC cell migration and invasion, as well as tumor formation and metastasis in nude mice. MiR-501-3p was verified to target TGFBR3. PDAC cells presented with down-regulated TGFBR3, which was further decreased in response to M2 macrophage treatment. TGF-β signaling pathway activation was implicated in the promotion of miR-501-3p in PDAC development. The suppression of macrophage-derived exosomal miR-501-3p resulted in the inhibition of tumor formation and metastasis in vivo.

Conclusion: M2 macrophage-derived exosomal miR-501-3p inhibits tumor suppressor TGFBR3 gene and facilitates the development of PDAC by activating the TGF-β signaling pathway, which provides novel targets for the molecular treatment of PDAC.

Keywords: Angiogenesis; Cell invasion; Exosome; M2 macrophage; Metastasis; MicroRNA-501-3p; Pancreatic ductal adenocarcinoma; TGF-β signaling pathway; TGFBR3.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Disease Progression
  • Exosomes / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Macrophages / cytology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Proteoglycans / genetics*
  • Receptors, Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / metabolism

Substances

  • MIRN501 microRNA, human
  • MicroRNAs
  • Proteoglycans
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • betaglycan