Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling

Int J Cancer. 2017 Oct 1;141(7):1389-1401. doi: 10.1002/ijc.30831. Epub 2017 Jun 24.

Abstract

Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies.

Keywords: C1QBP; IGF-1; hepatic metastasis; lipid rafts; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / secondary*
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Migration Assays
  • Cell Movement
  • Cell Proliferation
  • Chemotaxis
  • Cytoplasm / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Hyaluronan Receptors / metabolism
  • Insulin-Like Growth Factor I / metabolism*
  • Liver Neoplasms / secondary*
  • Membrane Microdomains / metabolism
  • Mice
  • Mice, Nude
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Proteins / metabolism*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Receptor, IGF Type 1 / metabolism*

Substances

  • C1QBP protein, human
  • CD44v6 antigen
  • Carrier Proteins
  • Hyaluronan Receptors
  • Mitochondrial Proteins
  • Neoplasm Proteins
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Receptor, IGF Type 1
  • Mitogen-Activated Protein Kinases