Expression of iron regulatory genes in a rat model of hepatocellular carcinoma.
OBJECTIVE
The altered iron metabolism in hepatocellular carcinomas (HCCs), characterized by the iron-deficient phenotype, is suggested to be of importance for tumour growth. However, the underlying molecular mechanisms remain poorly understood. We asked whether these iron perturbations would involve altered expression of genes controlling iron homeostasis.


METHODS
HCCs were induced in rats by the Solt and Farber protocol of chemical hepatocarcinogenesis, and to evaluate the effects of iron loading, one group of animals were supplemented with dietary iron during tumour progression. Tissue iron contents were determined, labelling indices of S-phase nuclei were calculated, and mRNA levels of iron-regulatory genes were quantitated. Protein levels of ferroportin1 were determined with Western blot.


RESULTS
HCCs displayed reduced amount of tissue iron and lack of histologically stainable iron. HCCs expressed significantly higher mRNA levels of genes involved in iron uptake (transferrin receptor-1, divalent metal ion transporter-1), ferroxidase activity (Ferritin-H), and iron extrusion (ferroportin1). The protein levels of ferroportin1 in iron-deficient HCCs were similar as in control livers, and did not increase in HCCs exposed to iron. Hepcidin mRNA levels were decreased in iron-deficient HCCs, rose in response to iron loading and correlated to the tissue iron content.


CONCLUSIONS
Taken together, the altered expressions of iron-regulatory genes in HCCs possibly reflect an increased demand for bioavailable iron and a high iron turnover in neoplastic cells.
Holmström
Petra
P
Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Gåfvels
Mats
M
Eriksson
Lennart C
LC
Dzikaite
Vijole
V
Hultcrantz
Rolf
R
Eggertsen
Gösta
G
Stål
Per
P
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics; D001052:Apoferritins / Q000096:biosynthesis / Q000235:genetics; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D015870:Gene Expression; D064451:Hepcidins; D035925:Iron-Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011990:Receptors, Transferrin / Q000096:biosynthesis / Q000235:genetics; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
D023181:Antimicrobial Cationic Peptides; D001052:Apoferritins; D027682:Cation Transport Proteins; D064451:Hepcidins; D035925:Iron-Regulatory Proteins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C578703:Hamp protein, rat