Ferritin heavy chain-mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial-mesenchymal transition.
The epithelial-mesenchymal transition (EMT) plays a critical role in tumor progression. To obtain a broad view of the molecules involved in EMT, we carried out a comparative proteomic analysis of transforming growth factor-beta1 (TGF-beta1)-induced EMT in AML-12 murine hepatocytes. A total of 36 proteins with significant alterations in abundance were identified. Among these proteins, ferritin heavy chain (FHC), a cellular iron storage protein, was characterized as a novel modulator in TGF-beta1-induced EMT. In response to TGF-beta1, there was a dramatic decrease in the FHC levels, which caused iron release from FHC and, therefore, increased the intracellular labile iron pool (LIP). Abolishing the increase in LIP blocked TGF-beta1-induced EMT. In addition, increased LIP levels promoted the production of reactive oxygen species (ROS), which in turn activated p38 mitogen-activated protein kinase. The elimination of ROS inhibited EMT, whereas H2O2 treatment rescued TGF-beta1-induced EMT in cells in which the LIP increase was abrogated. Overexpression of exogenous FHC attenuated the increases in LIP and ROS production, leading to a suppression of EMT. We also showed that TGF-beta1-mediated down-regulation of FHC occurs via 3' untranslated region-dependent repression of the translation of FHC mRNA. Moreover, we found that FHC down-regulation is an event that occurs between the early and highly invasive advanced stages in esophageal adenocarcinoma and that depletion of LIP or ROS suppresses the migration of tumor cells. Our data show that cellular iron homeostasis regulated by FHC plays a critical role in TGF-beta1-induced EMT.
Zhang
Ke-Hua
KH
Laboratory of Molecular Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Tian
Hong-Yu
HY
Gao
Xia
X
Lei
Wei-Wei
WW
Hu
Ying
Y
Wang
Dong-Mei
DM
Pan
Xin-Chao
XC
Yu
Mei-Lan
ML
Xu
Gen-Jun
GJ
Zhao
Fu-Kun
FK
Song
Jian-Guo
JG
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001052:Apoferritins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology* / Q000502:physiology; D004938:Esophageal Neoplasms / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D008648:Mesoderm / Q000166:cytology* / Q000502:physiology; D051379:Mice; D009369:Neoplasms / Q000473:pathology; D020543:Proteome; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology
D020543:Proteome; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D001052:Apoferritins; D007501:Iron