ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway

Biomed Pharmacother. 2018 Jan:97:1066-1077. doi: 10.1016/j.biopha.2017.11.034. Epub 2017 Nov 9.


Pituitary adenomas are the second most common primary brain tumor with invasive properties. We have previously identified that ADAM12 (a disintegrin and metalloprotease 12) overexpression is associated with the tumor invasion of pituitary adenomas, however, the underlying mechanism remains unknown. This study aims to elucidate the mechanistic role of ADAM12 in regulating the tumor invasion of pituitary adenomas. In this study, we first showed that ADAM12 expression was concomitant with epithelial to mesenchymal transition (EMT) process in clinical specimens of human pituitary adenomas. Further functional studies showed that ADAM12 silencing in pituitary adenoma cells significantly inhibited the EMT process and suppressed cell migration, invasion and proliferation without influencing cell apoptosis. Mechanistically, ADAM12 silencing significantly reduced ectodomain shedding of epidermal growth factor receptor (EGFR) ligands and attenuated the EGFR/ERK signaling pathway. Blocking of EGFR signaling resulted in EMT suppression similar to silencing of ADAM12 and reduced cell migration, invasion and proliferation, while EGFR activation abolished the suppression on EMT, proliferation, migration and invasion induced by ADAM12 silencing. Moreover, ADAM12 silencing significantly impaired tumorigenesis and EMT of pituitary adenoma cells in vivo. Taken together, our study provide crucial evidence that ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway. These finds strongly suggest that ADAM12 might serve as a novel valuable therapeutic target for pituitary adenomas.

Keywords: ADAM12; EMT; Invasion; Migration; Pituitary adenomas; Proliferation.

MeSH terms

  • ADAM12 Protein / genetics*
  • Adenoma / genetics*
  • Adenoma / pathology
  • Adult
  • Aged
  • Animals
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Epithelial-Mesenchymal Transition / genetics*
  • ErbB Receptors / metabolism
  • Female
  • Gene Silencing
  • Humans
  • MAP Kinase Signaling System / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness / genetics
  • Pituitary Neoplasms / genetics*
  • Pituitary Neoplasms / pathology
  • Signal Transduction / genetics
  • Xenograft Model Antitumor Assays
  • Young Adult


  • EGFR protein, human
  • ErbB Receptors
  • ADAM12 Protein
  • ADAM12 protein, human