Iron overload promotes Cyclin D1 expression and alters cell cycle in mouse hepatocytes.
OBJECTIVE
Patients exhibiting hepatic iron overload frequently develop hepatocellular carcinoma. An impaired expression of hepatic genes could be involved in this phenomenon. Our aim was to identify, during iron overload, hepatic genes involved in cell cycle which are misregulated.


RESULTS
Mouse iron overload was obtained by carbonyl-iron supplementation or iron-dextran injection. As expected, liver iron overload was associated to both hepatomegaly and hepatocyte polyploidisation. Hepatic gene expression was investigated using macroarray hybridizations. Cyclin D1 mRNA was the only gene whose expression increased in both models. Its overexpression was confirmed by real-time quantitative PCR. Immunobloting analysis demonstrated a strong increase of Cyclin D1 protein expression in iron-overloaded hepatocytes. This overexpression was correlated with early abnormalities in their cell cycle progression judged, in vitro, on DNA synthesis and mitotic index increase.


CONCLUSIONS
Our data demonstrates that Cyclin D1, a protein involved in G1-phase of cell cycle, is overexpressed in the iron-overloaded liver. This iron-induced expression of Cyclin D1 may contribute to development of cell cycle abnormalities, suggesting a role of Cyclin D1 in iron-related hepatocarcinogenesis.
Troadec
Marie-Bérengère
MB
INSERM U522, IFR 140, Université de Rennes 1, F-35033 Rennes, France.
Courselaud
Brice
B
Détivaud
Lénaïck
L
Haziza-Pigeon
Christelle
C
Leroyer
Patricia
P
Brissot
Pierre
P
Loréal
Olivier
O
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D019190:Iron Overload / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D019938:Cyclin D1