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Transferrin and transferrin receptor gene expression and iron uptake in hepatocellular carcinoma in the rat
Author(s) -
Pascale Rosa Maria,
De Miglio Maria Rosaria,
Muroni Maria Rosaria,
Simile Maria Maddalena,
Daino Lucia,
Seddaiu Maria Antonietta,
Pusceddu Stefano,
Gaspa Leonardo,
Calvisi Diego,
Manenti Giacomo,
Feo Francesco
Publication year - 1998
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510270220
Subject(s) - hccs , transferrin , hepatocellular carcinoma , transferrin receptor , biology , microbiology and biotechnology , endocrinology , medicine , cancer research
Iron plays an important role in cell growth and metabolism. In preneoplastic liver nodules, a rise in the number of transferrin receptors (Tf‐R) is associated with decreased endocytosis of the Fe 2 ‐Tf/Tf‐R complex. Because nodules are precursors of hepatocellular carcinoma (HCC), the question arises whether changes in iron uptake by nodules persist in HCC. Current work showed up‐regulation of Tf messenger RNA (mRNA) production in preneoplastic nodules, 12 to 37 weeks after initiation, and down‐regulation in atypical nodules (at 45 and 50 weeks) and HCCs, induced in rats by the “resistant hepatocyte” model. Tf‐R gene expression increased in nodules and HCCs. Tf‐R numbers increased, without changes in affinity constant, in HCC. Iron uptake was higher in HCC than in normal liver, 5 to 40 minutes after injection of 59 Fe 2 ‐Tf, with preferential accumulation in cytosol of tumor cells and in microsomes of normal liver. Purification through Percoll gradient of mitochondria plus lysosomes allowed the identification in liver and HCC of an endosomal compartment sequestering injected 125 I‐Tf. This subfraction was not seen when 59 Fe 2 ‐Tf was injected into rats, and 59 Fe was found in particulate material of both tissues. Liver and HCC exhibited comparable basal activities of plasma membrane NADH oxidase, an enzyme involved in iron uptake and cell growth. Stimulation of this activity by Fe 2 ‐Tf was higher in HCC than in normal liver. These results indicate that Tf expression may be a marker of preneoplastic liver progression to malignancy. Differently from nodules, HCC may sequester relatively high iron amounts, necessary for fast growth, both through the endocytic pathway and the reduced form of nicotinamide adenine dinucleotide (NADH) oxidase system.