ZIP4 regulates pancreatic cancer cell growth by activating IL-6/STAT3 pathway through zinc finger transcription factor CREB

Clin Cancer Res. 2010 Mar 1;16(5):1423-30. doi: 10.1158/1078-0432.CCR-09-2405. Epub 2010 Feb 16.


Purpose: Recent studies indicate a strong correlation of zinc transporter ZIP4 and pancreatic cancer progression; however, the underlying mechanisms are unclear. We have recently found that ZIP4 is overexpressed in pancreatic cancer. In this study, we investigated the signaling pathway through which ZIP4 regulates pancreatic cancer growth.

Experimental design: The expression of cyclin D1, interleukin 6 (IL-6), and signal transducer and activator of transcription 3 (STAT3) in pancreatic cancer xenografts and cells were examined by real-time PCR, Bio-Plex cytokine assay, and Western blot, respectively. The activity of cAMP response element-binding protein (CREB) is examined by a promoter activity assay.

Results: Cyclin D1 was significantly increased in the ZIP4 overexpressing MIA PaCa-2 cells (MIA-ZIP4)-injected orthotopic xenografts and was downregulated in the ZIP4-silenced ASPC-1 (ASPC-shZIP4) group. The phosphorylation of STAT3, an upstream activator of cyclin D1, was increased in MIA-ZIP4 cells and decreased in ASPC-shZIP4 cells. IL-6, a known upstream activator for STAT3, was also found to be significantly increased in the MIA-ZIP4 cells and xenografts and decreased in the ASPC-shZIP4 group. Overexpression of ZIP4 led to a 75% increase of IL-6 promoter activity and caused increased phosphorylation of CREB.

Conclusions: Our study suggest that ZIP4 overexpression causes increased IL-6 transcription through CREB, which in turn activates STAT3 and leads to increased cyclin D1 expression, resulting in increased cell proliferation and tumor progression in pancreatic cancer. These results elucidated a novel pathway in ZIP4-mediated pancreatic cancer growth and suggest new therapeutic targets, including ZIP4, IL-6, and STAT3, in pancreatic cancer treatment.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Cation Transport Proteins / metabolism*
  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclin D1 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-6 / metabolism*
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms / metabolism*
  • Phosphorylation
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / physiology*
  • Up-Regulation


  • Cation Transport Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Interleukin-6
  • SLC39A4 protein, human
  • STAT3 Transcription Factor
  • Cyclin D1