title: An important role of the hepcidin-ferroportin signaling in affecting tumor growth and metastasis.
abstract: Epidemiological and experimental studies have suggested that deregulated hepcidin-ferroportin (FPN) signaling is associated with the increased risk of cancers. However, the effects of deregulated hepcidin-FPN signaling on tumor behaviors such as metastasis and epithelial to mesenchymal transition (EMT) have not been closely investigated. In this study, LL/2 cancer cells were found to exhibit an impaired propensity to home into lungs, and a reduced ability to develop tumors was also demonstrated in lungs of Hamp1(-/-) mice. Moreover, hepatic hepcidin deficiency was found to considerably favor tumor-free survival in Hamp1(-/-) mice, compared with wild-type mice. These data thus underscored a contributive role of hepatic hepcidin in promoting lung cancer cell homing and fostering tumor progression. To explore the role of FPN in regulating tumor progression, we genetically engineered 4T1 cells with FPN over-expression upon induction by doxycycline. With this cell line, it was discovered that increased FPN expression reduced cell division and colony formation in vitro, without eliciting significant cell death. Analogously, FPN over-expression impeded tumor growth and metastasis to lung and liver in mice. At the molecular level, FPN over-expression was identified to undermine DNA synthesis and cell cycle progression. Importantly, FPN over-expression inhibited EMT, as reflected by the significant decrease of representative EMT markers, such as Snail1, Twist1, ZEB2, and vimentin. Additionally, there was also a reduction of lactate production in cells upon induction of FPN over-expression. Together, our results highlighted a crucial role of the hepcidin-FPN signaling in modulating tumor growth and metastasis, providing new evidence to understand the contribution of this signaling in cancers.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Weifang Medical College, Wendeng Central Hospital, Weihai 264400, China.
authors.forename: Daoqiang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Weifang Medical College, Wendeng Central Hospital, Weihai 264400, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Weifang Medical College, Wendeng Central Hospital, Weihai 264400, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Cong
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China sjliu@rcees.ac.cn.
authors.forename: Sijin
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D027682:Cation Transport Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D000098742:Ferroportin
keywords: cancer; epithelial to mesenchymal transition (EMT); ferroportin; hepcidin; iron; metastasis