The role of genetic factors in patients with hepatocellular carcinoma and iron overload – a prospective series of 234 patients

Funakoshi, Natalie; Chaze, I.; Alary, Anne‐Sophie; Tachon, Gaëlle; Cunat, Séverine; Giansily‐Blaizot, Muriel; Bismuth, Michaël; Larrey, Dominique; Pageaux, Georges‐Philippe; Schved, Jean‐François; Donnadieu‐Rigole, Hélène; Aguilar-Martinez, Patricia

doi:10.1111/liv.12984

Cited by 14 publications

(8 citation statements)

References 46 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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“…This study was a retrospective, single center study, and there was no information about the HH‐associated mutation profiles or blood iron levels of the subject patients. Our previous studies on the prevalence of the C282Y or S65C HFE mutation was 0% and only 8.5% for H63D heterozygotes in a Korean population; however, the mutation rates of the HFE ‐form or non‐ HFE ‐form of HH were not evaluated in this study; these could be genetic risk factors for iron overload among the HCC patients . Serum iron markers such as ferritin and transferrin or iron‐regulatory hormone hepcidin were also not examined in this study.…”

Section: Discussionmentioning

confidence: 85%

“…Our previous studies on the prevalence of the C282Y or S65C HFE mutation was 0% and only 8.5% for H63D heterozygotes in a Korean population; 12 however, the mutation rates of the HFE-form or non-HFE-form of HH were not evaluated in this study; these could be genetic risk factors for iron overload among the HCC patients. 33 Serum iron markers such as ferritin and transferrin or iron-regulatory hormone hepcidin were also not examined in this study. Nevertheless, this study has several strong points such as a relatively homogenous patient population consisting of curatively resected HCC patients, iron evaluation using surgical specimens with a sufficient tissue size, use of two different iron scoring methods, and a long follow-up of the subjects reliably showing the survival.…”

Section: Discussionmentioning

confidence: 99%

Hepatic iron overload in the portal tract predicts poor survival in hepatocellular carcinoma after curative resection

Chung

Shin²,

Kim

et al. 2017

Liver International

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“…It has been well established that patients with iron overload are at increased risk for HCC development. 22 In the presence of iron overload, iron staining reveals an extensive deposition of iron within cells of the non-tumour liver parenchyma, but no iron in the tumour tissue. 23 These results suggest that neoplastic hepatocytes have the potential to avoid excess iron accumulation in their cytoplasm for the purpose of cell survival.…”

Section: Discussionmentioning

confidence: 99%

“…It has been well established that patients with iron overload are at increased risk for HCC development . In the presence of iron overload, iron staining reveals an extensive deposition of iron within cells of the non‐tumour liver parenchyma, but no iron in the tumour tissue .…”

Section: Discussionmentioning

confidence: 99%

Transferrin receptor 1 overexpression is associated with tumour de‐differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma

et al. 2019

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Aim Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. An excess of iron in liver tissue causes oxidative stress, leading to hepatocellular carcinogenesis. Iron metabolism, which is regulated by a complex mechanism, is important for cancer cell survival. The aim of this study is to clarify the role of iron regulatory protein in the progression of HCC and in patient outcome. Methods and results We first investigated the mRNA level of iron metabolism‐related genes, including hepcidin, ferroportin 1 (FPN‐1) and transferrin receptor (TFR)‐1/2. TFR‐1/2 protein expression was then evaluated in surgical specimens from 210 cases using immunohistochemistry, and we compared clinicopathological factors with TFR‐1/2 expression. The mRNA expression levels of TFR‐1 were significantly increased in HCC tissues compared with adjacent non‐cancerous tissues (P = 0.0013), but there were no differences in other genes. High expression of TFR‐1 in HCC was associated with the absence of alcohol abuse (P = 0.0467), liver cirrhosis (P < 0.0001), higher alpha‐fetoprotein (AFP; P < 0.0001), smaller tumour size (P = 0.0022), poor histological differentiation (P < 0.0001) and morphological features (P < 0.0001). In contrast, high expression of TFR‐2 in HCC was associated with lower AFP (P < 0.0001), well‐differentiated histological grade (P < 0.0001) and morphological features (P = 0.0010). Multivariate analysis for both overall survival and recurrence‐free survival indicated that high TFR‐1 expression was a significant prognostic factor for poor outcome. Conclusions We found an inverse correlation of TFR‐1 and TFR‐2 expression in AFP and tumour differentiation. TFR‐1 overexpression suggests a higher risk of recurrence and death in HCC patients following liver resection.

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The role of genetic factors in patients with hepatocellular carcinoma and iron overload – a prospective series of 234 patients

Cited by 14 publications

References 46 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

Hepatic iron overload in the portal tract predicts poor survival in hepatocellular carcinoma after curative resection

Transferrin receptor 1 overexpression is associated with tumour de‐differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma

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