Analysis of HFE mutations and non‐HFE gene mutations (TFR2 and SLC40A1) in patients with phenotypic hemochromatosis from the basque country

Castiella, Agustín; Zapata, Eva; Juan, Ma; Zubiaurre, Leire; Iribarren, Arantxa; Otazua, Pedro; Fernández, José M.; Aragón, Larraitz; Zuriarrain, O.; Gorostidi, Ana

doi:10.1111/ijlh.12444

Cited by 5 publications

(2 citation statements)

References 13 publications

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“…The normal expression of SLC40A1 is essential to iron metabolism homeostasis. Moreover, many precious articles have revealed that abnormal iron metabolism induced by SLC40A1 mutation or intron sequence polymorphism is associated with autosomal dominant hemochromatosis, inflammatory reaction, and occurrence of liver cancer [ 17 – 22 ]. Our precious microarray data revealed that SLC40A1 was a potential downstream gene of Nrf2 [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Nrf2 induces cisplatin resistance via suppressing the iron export related gene SLC40A1 in ovarian cancer cells

Wu¹,

Bao²,

Zhang

et al. 2017

Oncotarget

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Induction of Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) has been demonstrated to be involved in cisplatin resistance in ovarian cancer. Solute carrier family 40 member 1 (SLC40A1) is an iron exporter, which possesses many putative Nrf2 binding sites. Here we hypothesize that it may be a possible downstream gene of Nrf2. Elevated level of Nrf2 and reduced level of SLC40A1 were found in cisplatin–resistant ovarian cancer cells as compared with cisplatin-sensitive ovarian cancer cells. Exogenous knockdown of Nrf2 leaded to increased expression of SLC40A1. While overexpression of Nrf2 resulted in decreased expression of SLC40A1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay revealed that Nrf2 inhibited the transcription of SLC40A1. Overexpression of SLC40A1 was able to reverse cisplatin resistance induced by Nrf2, while knockdown of SLC40A1 restored cisplatin resistance and increased iron concentration. Desferal, an iron chelator, was found to overcome cisplatin resistance through iron deprivation. Its function was boosted when combined with brusatol, an Nrf2 inhibitor. Taken together, this study first demonstrated that Nrf2 could transcriptionally suppress the expression of SLC40A1. Iron overload induced by SLC40A1 resulted in cisplatin resistance in ovarian cancer. Targeting iron metabolism may be a new therapeutic strategy to reverse drug resistance in ovarian cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Nrf2 induces cisplatin resistance via suppressing the iron export related gene SLC40A1 in ovarian cancer cells

Wu¹,

Bao²,

Zhang

et al. 2017

Oncotarget

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show abstract

“…FPN1 transcripts contain an IRE sequence in the 5′-UTR, which binds IRP proteins during iron deprivation, causing translational efficiency inhibition at the post-transcriptional level 15 . Many previous reports have revealed that FPN1 mutations and intron polymorphisms lead to hyperferritinemia, inflammatory reactions, and several cancers 16–18 . However, the biological effects of abnormal FPN1 expression on tumor behaviors and the molecular mechanisms underlying FPN1 dysregulation in multiple myeloma (MM) cells remain largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Ferroportin downregulation promotes cell proliferation by modulating the Nrf2–miR-17-5p axis in multiple myeloma

Kong

et al. 2019

Cell Death Dis

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Recent findings demonstrate that aberrant downregulation of the iron-exporter protein, ferroportin (FPN1), is associated with poor prognosis and osteoclast differentiation in multiple myeloma (MM). Here, we show that FPN1 was downregulated in MM and that clustered regularly interspaced short palindromic repeat (CRISPR)-mediated FPN1 knockout promoted MM cell growth and survival. Using a microRNA target-scan algorithm, we identified miR-17-5p as an FPN1 regulator that promoted cell proliferation and cell cycle progression, and inhibited apoptosis—both in vitro and in vivo. miR-17-5p inhibited retarded tumor growth in a MM xenograft model. Moreover, restoring FPN1 expression at least partially abrogated the biological effects of miR-17-5p in MM cells. The cellular iron concentration regulated the expression of the iron-regulatory protein (IRP) via the 5′-untranslated region of IRP messenger RNA and modulated the post-transcriptional stability of FPN1. Bioinformatics analysis with subsequent chromatin immunoprecipitation-polymerase chain reaction and luciferase activity experiments revealed that the transcription factor Nrf2 drove FPN1 transcription through promoter binding and suppressed miR-17-5p (which also increased FPN1 expression). Nrf2-mediated FPN1 downregulation promoted intracellular iron accumulation and reactive oxygen species. Our study links FPN1 transcriptional and post-transcriptional regulation with MM cell growth and survival, and validates the prognostic value of FPN1 and its utility as a novel therapeutic target in MM.

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Classification and structural analyses of mutational landscapes in hemochromatosis factor E protein: A protein defective in the hereditary hemochromatosis

et al. 2017

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Analysis of HFE mutations and non‐HFE gene mutations (TFR2 and SLC40A1) in patients with phenotypic hemochromatosis from the basque country

Cited by 5 publications

References 13 publications

Nrf2 induces cisplatin resistance via suppressing the iron export related gene SLC40A1 in ovarian cancer cells

Nrf2 induces cisplatin resistance via suppressing the iron export related gene SLC40A1 in ovarian cancer cells

Ferroportin downregulation promotes cell proliferation by modulating the Nrf2–miR-17-5p axis in multiple myeloma

Classification and structural analyses of mutational landscapes in hemochromatosis factor E protein: A protein defective in the hereditary hemochromatosis

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