抄録
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.
| 元の言語 | 英語 |
|---|---|
| ページ（範囲） | 950-965 |
| ページ数 | 16 |
| ジャーナル | Journal of Experimental Medicine |
| 巻 | 216 |
| 発行部数 | 4 |
| DOI | |
| 出版物ステータス | 出版済み - 4 1 2019 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Immunology
これを引用
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.
：: Journal of Experimental Medicine, 巻 216, 番号 4, 01.04.2019, p. 950-965.研究成果: ジャーナルへの寄稿 › 記事
}
TY - JOUR
T1 - Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis
AU - Muto, Yoshiharu
AU - Moroishi, Toshiro
AU - Ichihara, Kazuya
AU - Nishiyama, Masaaki
AU - Shimizu, Hideyuki
AU - Eguchi, Hidetoshi
AU - Moriya, Kyoji
AU - Koike, Kazuhiko
AU - Mimori, Koshi
AU - Mori, Masaki
AU - Katayama, Yuta
AU - Nakayama, Keiichi
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064189721&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064189721&partnerID=8YFLogxK
U2 - 10.1084/jem.20180900
DO - 10.1084/jem.20180900
M3 - Article
C2 - 30877170
AN - SCOPUS:85064189721
VL - 216
SP - 950
EP - 965
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -