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Iron-Siderophore and Tumorigenesis
Published in Debasis Bagchi, Manashi Bagchi, Metal Toxicology Handbook, 2020
Sayantan Maitra, Dibyendu Dutta
Ferric iron (Fe3+) is first converted into ferrous iron (Fe2+) by duodenal cytochrome b (DCYTB) and then imported into enterocytes via divalent metal transporter 1 (DMT1) which is a symporter present on the apical membrane of enterocytes. Iron (Fe2+) then exits the enterocyte by an efflux pump called ferroportin, integrated with oxidase hephaestin that helps to oxidize Fe2+ to Fe3+. Two atoms of Fe3+ then gets loaded onto transferrin (TF) in order to travel through bloodstream to get delivered to bone marrow or peripheral tissues. The diferric-transferrin (TF-[Fe3+]2) complex gets attached to transferrin receptor 1 (TFR1) present on the cell surface, and endocytosis of the complex takes place. Then the acidic condition of endosome triggers the dissociation of Fe3+ from TF, and the free Fe3+ is reduced to Fe2+ by six-transmembrane epithelial antigen of prostate (STEAP) reductase [10]. DMT1 then facilitates the transport of Fe2+ from endosome and forms a labile iron pool (LIP). Iron is then gets dispersed into multiple intracellular destinations and integrates into the active sites of enzymes that are involved in DNA synthesis, DNA repair, and cell cycle. Excess iron either stored in iron protein storage called ferritin or leaves the cell through ferroportin together with oxidase hephaestin [11,12].
Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes
Published in Journal of Toxicology and Environmental Health, Part A, 2019
F. Celsi, S. Crovella, R. R. Moura, M. Schneider, F. Vita, L. Finotto, G. Zabucchi, P. Zacchi, V. Borelli
Previously Crovella et al. (2016) identified in a population-based autopsy study three Fe metabolism-associated genes, significantly associated with protection against MPM while no association was found for NLRP1 and NLRP3 polymorphisms (Borelli et al. 2015). Our previous published results were confirmed (Crovella et al. 2016) by employing a different set of samples. The protective role of HEPH coding SNP (rs3747359) was confirmed as well as of the two non-coding SNPs, either in FTH or in TF (rs2715631 and rs76059597, respectively). Forgoing in silico analysis (Crovella et al. 2016) suggested a damaging effect of C substitution in HEPH gene which might impair hephaestin protein function; however, it was not possible to determine the putative functional impact related to the non-coding SNPs. Indeed, other databases (such as SROOGLE; http://sroogle.tau.ac.il/) were also examined for change in splice sites or SSC profiler (http://mirna.imbb.forth.gr/SSCprofiler.html) to check for miRNA genes, without reaching conclusive results. Since this finding, in spite of being replicated in a group of patients and controls coming from the same geographic area (Monfalcone, Italy), has not been published even in large GWAS studies, functional studies are strongly needed to confirm the impact of these genes and variation on susceptibility to mesothelioma.