Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation

Sci Rep. 2013;3:1870. doi: 10.1038/srep01870.

Abstract

Mesothelin (MSLN) and cancer antigen125/mucin 16 (CA125/MUC16) are potential biomarkers for pancreatic cancer (PC) that are co-overexpressed at the invading edges of PC tissues, and their expression correlates with poor survival rates. However, the role of MSLN-MUC16 molecular interaction in PC cell motility and invasion has yet to be elucidated. Using sophisticated bioengineering and molecular biology tools, we report that the binding of MSLN to MUC16 markedly enhances PC cell motility and invasion via the selective induction of matrix metalloproteinase (MMP)-7. MSLN-mediated MMP-7 upregulation in MUC16-expressing PC cells occurs via a p38 MAPK-dependent pathway. Depletion of MMP-7 or inhibition of p38 activity abolishes MSLN-mediated PC motility and invasion. These findings provide a novel perspective on the enhanced invasive potential associated with MSLN and MUC16 co-overexpression, and the mechanism underlying MMP-7 activation in PC invasion and metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Blotting, Western
  • CA-125 Antigen / genetics
  • CA-125 Antigen / metabolism*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Movement*
  • Cell Proliferation
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Matrix Metalloproteinase 7 / chemistry
  • Matrix Metalloproteinase 7 / genetics
  • Matrix Metalloproteinase 7 / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mesothelin
  • Neoplasm Invasiveness
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • CA-125 Antigen
  • GPI-Linked Proteins
  • MSLN protein, human
  • MUC16 protein, human
  • Membrane Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • p38 Mitogen-Activated Protein Kinases
  • MMP7 protein, human
  • Matrix Metalloproteinase 7
  • Mesothelin