HFE genotype affects exosome phenotype in cancer

Mrowczynski, Oliver; Madhankumar, A.B.; Slagle‐Webb, Becky; Lee, Sang Yong; Zacharia, Brad E.; Connor, James R.

doi:10.1016/j.bbagen.2017.05.014

Cited by 13 publications

(9 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Subsequently Truman-Rosentsvit et al found that in addition to the lysosomal secretory pathway, ferritin can also be secreted via the multivesicular body-exosome pathway [30]. Consistent with the secretion in membrane bound vesicles, Mrowcyznski et al has demonstrated the presence of H-ferritin in exosomes [31]. Recently, Kimura et al have further described this secretion mechanism as dependent upon the tripartite motif containing 16 (TRIM16) secretory autophagy receptor, avoiding autolysosomal degradation by pivoting ferritin cargo to the plasma membrane for secretion [32].…”

Section: Ferritin As An Iron Delivery Proteinmentioning

confidence: 99%

Emerging and Dynamic Biomedical Uses of Ferritin

Chiou

Connor

2018

Pharmaceuticals

View full text Add to dashboard Cite

Ferritin, a ubiquitously expressed protein, has classically been considered the main iron cellular storage molecule in the body. Owing to the ferroxidase activity of the H-subunit and the nucleation ability of the L-subunit, ferritin can store a large amount of iron within its mineral core. However, recent evidence has demonstrated a range of abilities of ferritin that extends well beyond the scope of iron storage. This review aims to discuss novel functions and biomedical uses of ferritin in the processes of iron delivery, delivery of biologics such as chemotherapies and contrast agents, and the utility of ferritin as a biomarker in a number of neurological diseases.

show abstract

Section: Ferritin As An Iron Delivery Proteinmentioning

confidence: 99%

Emerging and Dynamic Biomedical Uses of Ferritin

Chiou

Connor

2018

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“… 8 Ferritin is the major intracellular iron storage protein 9,10 and is also found extracellularly in EVs. 11,12 …”

Section: Introductionmentioning

confidence: 99%

CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles

Izumi

Richardson

Dhekne

et al. 2021

Blood

View full text Add to dashboard Cite

Extracellular vesicles (EVs) transfer functional molecules between cells. CD63 is a widely recognized EV marker that contributes to EV secretion from cells. However, the regulation of its expression remains largely unknown. Ferritin is a cellular iron storage protein that can be also secreted by the exosome pathway (Truman-Rosentsvit M. et al. BLOOD 131 (2018) 342-352), with serum ferritin levels classically reflecting body iron stores. Iron metabolism-associated proteins, such as ferritin, are intricately regulated by cellular iron levels via the iron responsive element (IRE)-iron regulatory protein (IRP) system. Herein, we present a novel mechanism demonstrating that the expression of the EV-associated protein, CD63, is under the regulation of the IRE-IRP system. We discovered a canonical IRE in the 5'-untranslated region (UTR) of CD63 mRNA responsible for regulating its expression in response to increased iron. Cellular iron-loading caused a marked increase in CD63 expression and the secretion from cells of CD63 positive (i.e., CD63(+)) EVs, which were shown to contain ferritin-H (FtH) and -L (FtL). Our results demonstrate that under iron-loading, intracellular ferritin is transferred via nuclear receptor coactivator 4 (NCOA4) to CD63(+) EVs that are then secreted. Such iron-regulated secretion of the major iron storage protein ferritin via CD63(+) EVs, poses significant impact for understanding the local cell-to-cell exchange of ferritin and iron.

show abstract

“…There are many reports for the function of H63D or C282Y HFE in human cancer. For example, at the cellular level, the HFE H63D variant alters cholesterol metabolism [47], Endoplasmic Reticulum stress [48] and alters cancer phenotype [41, 49] including the protein profiles of exosomes [50]. Mouse H67D Hfe variant (human equivalent for H63D HFE variant) also alters macrophage function [51].…”

Section: Discussionmentioning

confidence: 99%

Impact of HFE variants and sex in lung cancer

et al. 2019

Self Cite

View full text Add to dashboard Cite

The homeostatic iron regulator protein HFE is involved in regulation of iron acquisition for cells. The prevalence of two common HFE gene variants (H63D, C282Y) has been studied in many cancer types; however, the impact of HFE variants, sex and HFE gene expression in lung cancer has not been studied. We determined the prevalence of HFE variants and their impact on cancer phenotypes in lung cancer cell lines, in lung cancer patient specimens, and using The Cancer Genome Atlas (TCGA) database. We found that seven out of ten human lung cancer cell lines carry the H63D or C282Y HFE variant. Analysis of lung cancer specimens from our institute (Penn State Hershey Medical Center) revealed a sex and genotype interaction risk for metastasis in lung adenocarcinoma (LUAD) patients; H63D HFE is associated with less metastasis in males compared to wild type (WT) HFE; however, females with the H63D HFE variant tend to develop more metastatic tumors than WT female patients. In the TCGA LUAD dataset, the H63D HFE variant was associated with poorer survival in females compared to females with WT HFE. The frequency of C282Y HFE is higher in female lung squamous cell carcinoma (LUSC) patients of TCGA than males, however the C282Y HFE variant did not impact the survival of LUSC patients. In the TCGA LUSC dataset, C282Y HFE patients (especially females) had poorer survival than WT HFE patients. HFE expression level was not affected by HFE genotype status and did not impact patient’s survival, regardless of sex. In summary, these data suggest that there is a sexually dimorphic effect of HFE polymorphisms in the survival and metastatic disease in lung cancer.

show abstract

HFE genotype affects exosome phenotype in cancer

Cited by 13 publications

References 38 publications

Emerging and Dynamic Biomedical Uses of Ferritin

Emerging and Dynamic Biomedical Uses of Ferritin

CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles

Impact of HFE variants and sex in lung cancer

Contact Info

Product

Resources

About