title: Hemochromatosis enhances tumor progression via upregulation of intracellular iron in head and neck cancer.
abstract: BACKGROUND
  Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), outcomes have not significantly improved; highlighting the importance of identifying novel therapeutic approaches to target this disease. To address this challenge, we proceeded to evaluate the role of iron in HNSCC.
  
  
  METHODS
  Expression levels of iron-related genes were evaluated in HNSCC cell lines using quantitative RT-PCR. Cellular phenotypic effects were assessed using viability (MTS), clonogenic survival, BrdU, and tumor formation assays. The prognostic significance of iron-related proteins was determined using immunohistochemistry.
  
  
  RESULTS
  In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. In vitro knockdown of HFE in HNSCC cell lines significantly decreased hepcidin (HAMP) expression and intracellular iron level. This in turn, resulted in a significant decrease in HNSCC cell viability, clonogenicity, DNA synthesis, and Wnt signalling. These cellular changes were reversed by re-introducing iron back into HNSCC cells after HFE knockdown, indicating that iron was mediating this phenotype. Concordantly, treating HNSCC cells with an iron chelator, ciclopirox olamine (CPX), significantly reduced viability and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression.
  
  
  CONCLUSIONS
  Our data identify HFE as potentially novel prognostic marker in HNSCC that promotes tumour progression via HAMP and elevated intracellular iron levels, leading to increased cellular proliferation and tumour formation. Hence, these findings suggest that iron chelators might have a therapeutic role in HNSCC management.
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lenarduzzi
authors.forename: Angela B Y
authors.initials: AB
authors.lastname: Hui
authors.forename: Shijun
authors.initials: S
authors.lastname: Yue
authors.forename: Emma
authors.initials: E
authors.lastname: Ito
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Justin
authors.initials: J
authors.lastname: Williams
authors.forename: Jeff
authors.initials: J
authors.lastname: Bruce
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakemura-Nakatsugawa
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Aaron
authors.initials: A
authors.lastname: Schimmer
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
mesh_terms: D018450:Disease Progression; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006432:Hemochromatosis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D007501:Iron