Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis

Yoshiharu Muto, Toshiro Moroishi, Kazuya Ichihara, Masaaki Nishiyama, Hideyuki Shimizu, Hidetoshi Eguchi, Kyoji Moriya, Kazuhiko Koike, Koshi Mimori, Masaki Mori, Yuta Katayama, Keiichi Nakayama

Research output: Contribution to journalArticle

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Abstract

Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload elicited by FBXL5 ablation gave rise to oxidative stress, tissue damage, inflammation, and compensatory proliferation of hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting outcome of FBXL5 deficiency in the liver was also found to be effective in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis promoted by iron overload. In addition, dysregulation of FBXL5-mediated cellular iron homeostasis was found to be associated with poor prognosis in human HCC, suggesting that FBXL5 plays a key role in defense against hepatocarcinogenesis.

Original languageEnglish
Pages (from-to)950-965
Number of pages16
JournalJournal of Experimental Medicine
Volume216
Issue number4
DOIs
Publication statusPublished - Apr 1 2019

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Carcinogenesis
Homeostasis
Iron
Iron Overload
Liver
Hepatocellular Carcinoma
Ligases
Ubiquitin
Carcinogens
Hepatocytes
Oxidative Stress
Viruses
Inflammation
Neoplasms

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis. / Muto, Yoshiharu; Moroishi, Toshiro; Ichihara, Kazuya; Nishiyama, Masaaki; Shimizu, Hideyuki; Eguchi, Hidetoshi; Moriya, Kyoji; Koike, Kazuhiko; Mimori, Koshi; Mori, Masaki; Katayama, Yuta; Nakayama, Keiichi.

In: Journal of Experimental Medicine, Vol. 216, No. 4, 01.04.2019, p. 950-965.

Research output: Contribution to journalArticle

Muto, Y, Moroishi, T, Ichihara, K, Nishiyama, M, Shimizu, H, Eguchi, H, Moriya, K, Koike, K, Mimori, K, Mori, M, Katayama, Y & Nakayama, K 2019, 'Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis', Journal of Experimental Medicine, vol. 216, no. 4, pp. 950-965. https://doi.org/10.1084/jem.20180900
Muto Y, Moroishi T, Ichihara K, Nishiyama M, Shimizu H, Eguchi H et al. Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis. Journal of Experimental Medicine. 2019 Apr 1;216(4):950-965. https://doi.org/10.1084/jem.20180900
Muto, Yoshiharu ; Moroishi, Toshiro ; Ichihara, Kazuya ; Nishiyama, Masaaki ; Shimizu, Hideyuki ; Eguchi, Hidetoshi ; Moriya, Kyoji ; Koike, Kazuhiko ; Mimori, Koshi ; Mori, Masaki ; Katayama, Yuta ; Nakayama, Keiichi. / Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis. In: Journal of Experimental Medicine. 2019 ; Vol. 216, No. 4. pp. 950-965.
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