ZIP4 upregulates the expression of neuropilin-1, vascular endothelial growth factor, and matrix metalloproteases in pancreatic cancer cell lines and xenografts.

We have recently found that a zinc transporter, ZIP4, is overexpressed in human pancreatic cancer and contributes to pancreatic cancer pathogenesis and progression. However, the detailed mechanism that how ZIP4 regulates pancreatic cancer growth is not clear. In this study, we further investigated the key molecules regulated by ZIP4 in pancreatic cancer angiogenesis and metastasis. We found that overexpression of ZIP4 caused significantly increased expression of NRP-1, VEGF, MMP-2 and MMP-9 in both pancreatic cancer cell lines and xenografts. Conversely, silencing of ZIP4 by short hairpin RNA (shRNA) was associated with decreased expression of NRP-1 and VEGF in pancreatic cancer xenografts. The ZIP4 expression and NRP-1 level are also correlated in established human pancreatic cancer cell lines. These results indicate that ZIP4-mediated pancreatic cancer growth might involve angiogenesis, invasion and metastasis pathways, and NRP-1, VEGF and MMPs are important intermediate molecules in transducing the ZIP4 initiated signal cascades in pancreatic cancer.