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The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value.

ABSTRACT: Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is hepcidin (Hepc), which is a powerful iron absorption inhibitor mainly produced by the liver. Transferrin receptor 2 (Tfr2) is one of the hepcidin regulators, and mutations in TFR2 gene are responsible for type 3 hereditary hemochromatosis (HFE3), a genetically heterogeneous disease characterized by systemic iron overload. It has been recently pointed out that Hepc production and iron regulation could be exerted also in tissues other than liver, and that Tfr2 has an extrahepatic role in iron metabolism as well. This review summarizes all the most recent data on Tfr2 extrahepatic role, taking into account the putative distinct roles of the two main Tfr2 isoforms, Tfr2? and Tfr2?. Representing Hepc modulation an effective approach to correct iron balance impairment in common human diseases, and with Tfr2 being one of its regulators, it would be worthwhile to envisage Tfr2 as a therapeutic target.

SUBMITTER: Roetto A

PROVIDER: S-EPMC6316356 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value.

Roetto Antonella A Mezzanotte Mariarosa M Pellegrino Rosa Maria RM

Pharmaceuticals (Basel, Switzerland) 20181023 4

Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is hepcidin (Hepc), which is a powerful iron absorption inhibitor mainly produced by the liver. Transferrin receptor 2 (Tfr2) is one of the hepcidin regulators, and mutations in <i>TFR2</i> gene are responsible for type 3 hereditary ...[more]

PMID: 30360575

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Project description:Astrocytic brain tumors are the most frequent primary brain tumors. Treatment with radio- and chemotherapy has increased survival making prognostic biomarkers increasingly important. The aim of the present study was to investigate the expression and prognostic value of transferrin receptor-1 (TfR1) as well as ferritin heavy (FTH) and light (FTL) chain in astrocytic brain tumors. A cohort of 111 astrocytic brain tumors (grade II-IV) was stained immunohistochemically with antibodies against TfR1, FTH, and FTL and scored semi-quantitatively. Double-immunofluorescence stainings were established to determine the phenotype of cells expressing these markers. We found that TfR1, FTH, and FTL were expressed by tumor cells in all grades. TfR1 increased with grade (p<0.001), but was not associated with prognosis in the individual grades. FTH and FTL were expressed by tumor cells and cells with microglial/macrophage morphology. Neither FTH nor FTL increased with malignancy grade, but low FTH expression by both tumor cells (p = 0.03) and microglia/macrophages (p = 0.01) correlated with shorter survival in patients anaplastic astrocytoma. FTL-positive microglia/macrophages were frequent in glioblastomas, and high FTL levels correlated with shorter survival in the whole cohort (p = 0.01) and in patients with anaplastic astrocytoma (p = 0.02). Double-immunofluorescence showed that TfR1, FTH, and FTL were co-expressed to a limited extent with the stem cell-related marker CD133. FTH and FTL were also co-expressed by IBA-1-positive microglia/macrophages. In conclusion, TfR1 was highly expressed in glioblastomas and associated with shorter survival in the whole cohort, but not in the individual malignancy grades. Low levels of FTH-positive tumor cells and microglia/macrophages were associated with poor survival in anaplastic astrocytomas, while high amounts of FTL-positive microglia/macrophages had a negative prognostic value. The results suggest that regulation of the iron metabolism in astrocytic brain tumors is complex involving both autocrine and paracrine signaling.

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The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value.

Publications

The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value.

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