ZIP4 silencing improves bone loss in pancreatic cancer

Oncotarget. 2015 Sep 22;6(28):26041-51. doi: 10.18632/oncotarget.4667.


Metabolic bone disorders are associated with several types of human cancers. Pancreatic cancer patients usually suffer from severe nutrition deficiency, muscle wasting, and loss of bone mass. We have previously found that silencing of a zinc transporter ZIP4 prolongs the survival and reduces the severity of the cachexia in vivo. However, the role of ZIP4 in the pancreatic cancer related bone loss remains unknown. In this study we investigated the effect of ZIP4 knockdown on the bone structure, composition and mechanical properties of femurs in an orthotopic xenograft mouse model. Our data showed that silencing of ZIP4 resulted in increased bone tissue mineral density, decreased bone crystallinity and restoration of bone strength through the RANK/RANKL pathway. The results further support the impact of ZIP4 on the progression of pancreatic cancer, and suggest its potential significance as a therapeutic target for treating patients with such devastating disease and cancer related disorders.

Keywords: RANK/RANKL signaling; ZIP4; bone; cachexia; pancreatic cancer.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Density
  • Bone Resorption / genetics*
  • Bone Resorption / metabolism
  • Bone Resorption / therapy
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Femur / metabolism
  • Femur / pathology
  • Femur / physiopathology
  • Humans
  • Male
  • Mechanical Phenomena
  • Mice, Nude
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / therapy
  • RANK Ligand / metabolism
  • RNA Interference*
  • RNAi Therapeutics / methods
  • Receptor Activator of Nuclear Factor-kappa B / metabolism
  • X-Ray Microtomography
  • Xenograft Model Antitumor Assays


  • Cation Transport Proteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • SLC39A4 protein, human
  • TNFRSF11A protein, human