Chronic exposure to excess iron promotes EMT and cancer via p53 loss in pancreatic cancer

作     者：Yangzom D.Bhutia Jiro Ogura Paul J.Grippo Carolina Torres Toshihiro Sato Mitchell Wachtel Sabarish Ramachandran Ellappan Babu Sathish Sivaprakasam Devaraja Rajasekaran Bradley Schniers Nhu On Logan Smoot Muthusamy Thangaraju Jaya P.Gnana-Prakasam Vadivel Ganapathy Yangzom D.Bhutia;Jiro Ogura;Paul J.Grippo;Carolina Torres;Toshihiro Sato;Mitchell Wachtel;Sabarish Ramachandran;Ellappan Babu;Sathish Sivaprakasam;Devaraja Rajasekaran;Bradley Schniers;Nhu On;Logan Smoot;Muthusamy Thangaraju;Jaya P.Gnana-Prakasam;Vadivel Ganapathy

作者机构：Department of Cell Biology and BiochemistryTexas Tech University Health Sciences CenterLubbockTX 79430USA Department of Pharmaceutical SciencesTohoku University Hospital1-1 Seiryo-machiAoba-kuSendaiMiyagi 980-8574Japan Department of MedicineUniversity of Illinois at ChicagoChicagoIL 60607USA Department of Surgical PathologyTexas Tech University Health Sciences CenterLubbockTX 79430USA Department of Biological SciencesTexas Tech UniversityLubbockTX 79410USA Department of Chemistry and BiochemistryTexas Tech UniversityLubbockTX 79410USA Department of Biochemistry and Molecular BiologyAugusta UniversityAugustaGA 30912USA Department of OphthalmologySt.Louis UniversitySt.LouisMO 63104USA 

出 版 物：《Asian Journal of Pharmaceutical Sciences》 (亚洲药物制剂科学（英文）)

年 卷 期：2020年第15卷第2期

页      面：237-251页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：The authors acknowledge the financial support received from the National Institute of Health(CA223271) The authors would also like to thank Dr.Ming Tsao(Ontario Cancer Institute)for the human pancreatic ductal epithelial(HPDE)cell line 

主　　题：SLC7A11 p53 Iron Heme Epithelial-mesenchymal transition 

摘      要：Based on the evidence that hemochromatosis, an iron-overload disease, drives hepatocellular carcinoma, we hypothesized that chronic exposure to excess iron, either due to genetic or environmental causes, predisposes an individual to cancer. Using pancreatic cancer as our primary focus, we employed cell culture studies to interrogate the connection between excess iron and cancer, and combined in vitro and in vivo studies to explore the connection further. Ferric ammonium citrate was used as an exogenous iron source. Chronic exposure to excess iron induced epithelial-mesenchymal transition(EMT) in normal and cancer cell lines, loss of p53, and suppression of p53 transcriptional activity evidenced from decreased expression of p53 target genes(p21, cyclin D1, Bax, SLC7A11). To further extrapolate our cell culture data, we generated EL-KrasG12D( EL-Kras) mouse(pancreatic neoplastic mouse model) expressing Hfe+/+ and Hfe-/- genetic background. p53 target gene expression decreased in EL-Kras/Hfe-/- mouse pancreas compared to EL-Kras/Hfe+/+ mouse pancreas. Interestingly, the incidence of acinar-to-ductal metaplasia and cystic pancreatic neoplasms(CPN) decreased in EL-Kras/Hfe-/- mice, but the CPNs that did develop were larger in these mice than in EL-Kras/Hfe+/+ mice. In conclusion, these in vitro and in vivo studies support a potential role for chronic exposure to excess iron as a promoter of more aggressive disease via p53 loss and SLC7A11 upregulation within pancreatic epithelial cells.