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Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype.

ABSTRACT: High levels of iron in the peritoneal cavity during menstruation have been implicated in the pathogenesis of endometriosis. However, whether iron directly affects the growth or migration of human endometriotic cells is poorly understood. This study demonstrated the presence of increased levels of the iron storage protein, ferritin, in the endometriotic tissues of patients with endometriosis. Furthermore, iron treatment stimulated the migration and epithelial-mesenchymal transition (EMT), but not growth, of 12Z human endometriotic cells. The expression of matrix metalloproteinase (MMP)-2/-9 was markedly increased through iron treatment in 12Z cells. Interestingly, intracellular reactive oxygen species (ROS) levels were significantly increased by iron in 12Z cells, and N-acetyl-L-cysteine significantly reduced iron-induced migration and MMP-2/-9 expression. Additionally, iron stimulated the activation of the NF?B pathway, and the activation was associated with iron-induced migration and MMP-2/-9 expression in 12Z cells. Moreover, iron markedly increased EMT and MMP-2/-9 expression in endometriotic lesions in an endometriosis mouse model. Taken together, these results suggest that iron may contribute to the migration abilities of human endometriotic cells via MMP expression through the ROS-NF?B pathway.

SUBMITTER: Woo JH

PROVIDER: S-EPMC7694081 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype.

Woo Jeong-Hwa JH Choi Youn Seok YS Choi Jung-Hye JH

Biomedicines 20201027 11

High levels of iron in the peritoneal cavity during menstruation have been implicated in the pathogenesis of endometriosis. However, whether iron directly affects the growth or migration of human endometriotic cells is poorly understood. This study demonstrated the presence of increased levels of the iron storage protein, ferritin, in the endometriotic tissues of patients with endometriosis. Furthermore, iron treatment stimulated the migration and epithelial-mesenchymal transition (EMT), but not ...[more]

PMID: 33121166

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Project description:BACKGROUND: Iron is essential for the maintenance of basic cellular processes. In the regulation of its cellular levels, ferritin acts as the main intracellular iron storage protein. In this work we present a mathematical model for the dynamics of iron storage in ferritin during the process of intestinal iron absorption. A set of differential equations were established considering kinetic expressions for the main reactions and mass balances for ferritin, iron and a discrete population of ferritin species defined by their respective iron content. RESULTS: Simulation results showing the evolution of ferritin iron content following a pulse of iron were compared with experimental data for ferritin iron distribution obtained with purified ferritin incubated in vitro with different iron levels. Distinctive features observed experimentally were successfully captured by the model, namely the distribution pattern of iron into ferritin protein nanocages with different iron content and the role of ferritin as a controller of the cytosolic labile iron pool (cLIP). Ferritin stabilizes the cLIP for a wide range of total intracellular iron concentrations, but the model predicts an exponential increment of the cLIP at an iron content > 2,500 Fe/ferritin protein cage, when the storage capacity of ferritin is exceeded. CONCLUSIONS: The results presented support the role of ferritin as an iron buffer in a cellular system. Moreover, the model predicts desirable characteristics for a buffer protein such as effective removal of excess iron, which keeps intracellular cLIP levels approximately constant even when large perturbations are introduced, and a freely available source of iron under iron starvation. In addition, the simulated dynamics of the iron removal process are extremely fast, with ferritin acting as a first defense against dangerous iron fluctuations and providing the time required by the cell to activate slower transcriptional regulation mechanisms and adapt to iron stress conditions. In summary, the model captures the complexity of the iron-ferritin equilibrium, and can be used for further theoretical exploration of the role of ferritin in the regulation of intracellular labile iron levels and, in particular, as a relevant regulator of transepithelial iron transport during the process of intestinal iron absorption.

Dataset Information

Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype.

Publications

Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype.

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