Journal
EMBO MOLECULAR MEDICINE
Volume 5, Issue 9, Pages 1322-1334Publisher
WILEY
DOI: 10.1002/emmm.201302507
Keywords
microRNA-373; pancreatic cancer; zinc; ZIP4
Categories
Funding
- National Institutes of Health (NIH) [R01CA138701, R21CA133604]
- William and Ella Owens Medical Research Foundation
- Mayo Clinic Pancreatic SPORE [P50 CA102701]
- Mayo Clinic Center for Cell Signaling in Gastroenterology [P30 DK84567]
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Changes in the intracellular levels of the essential micronutrient zinc have been implicated in multiple diseases including pancreatic cancer; however, the molecular mechanism is poorly understood. Here, we report a novel mechanism where increased zinc mediated by the zinc importer ZIP4 transcriptionally induces miR-373 in pancreatic cancer to promote tumour growth. Reporter, expression and chromatin immunoprecipitation assays demonstrate that ZIP4 activates the zinc-dependent transcription factor CREB and requires this transcription factor to increase miR-373 expression through the regulation of its promoter. miR-373 induction is necessary for efficient ZIP4-dependent enhancement of cell proliferation, invasion, and tumour growth. Further analysis of miR-373 in vivo oncogenic function reveals that it is mediated through its negative regulation of TP53INP1, LATS2 and CD44. These results define a novel ZIP4-CREB-miR-373 signalling axis promoting pancreatic cancer growth, providing mechanistic insights explaining in part how a zinc transporter functions in cancer cells and may have broader implications as inappropriate regulation of intracellular zinc levels plays an important role in many other diseases.
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