Liver Iron, HFE Gene Mutations, and Hepatocellular Carcinoma Occurrence in Patients With Cirrhosis

Nahon, Pierre; Sutton, Angéla; Rufat, Pierre; Ziol, Marianne; Thabut, Gabriel; Schischmanoff, Pierre-Olivier; Vidaud, Dominique; Charnaux, Nathalie; Couvert, Philippe; Ganne‐Carrié, Nathalie; Trinchet, Jean–Claude; Gattegno, Liliane; Beaugrand, Michel

doi:10.1053/j.gastro.2007.10.038

Cited by 119 publications

(98 citation statements)

References 28 publications

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“…Despite similar demographic features and prevalence of viral hepatitis, the MDM2 mutated G allele was significantly associated with alcohol abuse (P ϭ 0.02) and the presence of HFE mutations (P ϭ 0.05), known risk factors for iron overload in patients with cirrhosis 4,69 (Table 3). These data suggest an interaction between high MDM2 levels, low p53 activity, and iron overload in the pathogenesis of HCC.…”

Section: Association Between the ϫ309 T ͼ G Mdm2 Promoter Polymorphismentioning

confidence: 98%

“…In conclusion, iron status influences p53 activity and antioxidant response by modulating Hepatocellular iron accumulation, either genetic due to hereditary hemochromatosis (HH) or acquired due to alcohol abuse, chronic hepatitis C virus infection, or porphyria cutanea tarda, is a frequent cause of liver damage and has been associated with increased risk of developing hepatocellular carcinoma (HCC), a leading cause of cancer related death worldwide. [1][2][3][4] Furthermore, increased iron stores have been reported to be a risk factor for other neoplasia, such as breast and colon cancer, 5 whereas iron reduction therapy has been associated with a decreased incidence of cancer. 6 A role for iron overload in HCC development is supported by several lines of evidence including increased concentrations of iron in non-neoplastic liver tissue of patients who underwent liver transplantation for liver cancer, 7 and an augmented risk of developing liver cancer in patients with HH.…”

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confidence: 99%

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Iron-Dependent Regulation of MDM2 Influences p53 Activity and Hepatic Carcinogenesis

Dongiovanni

Fracanzani

Cairo

et al. 2010

The American Journal of Pathology

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Iron overload is a risk factor for hepatocarcinoma, but the pathways involved are poorly characterized. Gene expression analysis in immortalized mouse hepatocytes exposed to iron or the iron chelator deferoxamine revealed that iron downregulated, whereas deferoxamine upregulated, mRNA levels of mouse double minute gene 2 (MDM2), the ubiquitin ligase involved in the degradation of the oncosuppressor p53. Regulation of MDM2 by iron status was observed at protein levels in mouse hepatocytes and rat liver, and was associated with specular changes in p53 expression. Iron dependent regulation of MDM2/ p53 was confirmed ex-vivo in human monocytes, by manipulation of iron pool and in a genetic model of iron deficiency, leading to modulation of p53 target genes involved in the antioxidant response and apoptosis. Iron status influenced p53 ubiquitination and degradation rate, and the MDM2 inhibitor nutlin increased p53 levels in iron-depleted cells. Furthermore, nutlin enhanced the antiproliferative activity of deferoxamine in HepG2 hepatoblastoma cells. The MDM2 ؊309T > G promoter polymorphism, determining increased MDM2 and lower p53 activity, was associated with higher risk of hepatocarcinoma in cirrhotic patients with hemochromatosis, and with HFE mutations in patients with hepatocarcinoma without hemochromatosis, suggesting an interaction between MDM2 and iron in the pathogenesis of hepatocarcinoma. In conclusion, iron status influences p53 activity and antioxidant response by modulating MDM2 expression. MDM2 inhibitors may enhance the antiproliferative activity of iron chelators. (Am J Pathol

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Section: Association Between the ϫ309 T ͼ G Mdm2 Promoter Polymorphismentioning

confidence: 98%

mentioning

confidence: 99%

Iron-Dependent Regulation of MDM2 Influences p53 Activity and Hepatic Carcinogenesis

Dongiovanni

Fracanzani

Cairo

et al. 2010

The American Journal of Pathology

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“…These genetic traits are capable of modulating several biological pathways involved in hepatocarcinogenesis, such as inflammation [63,64], oxidative stress [65,66], and iron [67,68] or lipid metabolism [69]. In this setting, other genetic modifiers of lipid turnover seem to impact HCC risk in association with PNPLA3 genotype.…”

Section: Pnpla3 In the Complex Genetic Heterogeneity Influencing Livementioning

confidence: 99%

PNPLA3 gene in liver diseases

Trépo

Romeo

Zucman‐Rossi

et al. 2016

Journal of Hepatology

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214

187

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“…16 In addition, it has been shown that patients with polymorphisms of oxidant/antioxidant enzymes were at increased risk of cancer. 17 Similarly, it has been reported that the risk of HCC is higher in patients who have nonalcoholic steatohepatitis (NASH)-related cirrhosis with hepatic iron excess.…”

Section: Iron As a Cofactor In The Pathogenesis Of Hccmentioning

confidence: 99%