Do cancer cells selectively mutate HFE to increase their intracellular iron?
Malignant cells compared to their normal counter-parts, have an increased requirement for iron in order to achieve an enhanced cell growth. Transferrin receptor (TfR), an essential transport protein that enables cells to satisfy their need of iron, is upregulated in cancer cells. The hemochromatosis gene (HFE) produces a protein that interacts with TfR; and we hypothesized that tumor cells would selectively mutate HFE to improve their iron-uptake and thus provide themselves a growth advantage over non-tumor cells. A total of 36 non-small cell lung cancer (NSCLC) samples and matched tumor-free tissue from the same individuals were examined for HFE mutations using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Sequencing analysis of the shifted bands in three of 36 cases (in both, the tumor and matching normal tissue of the same individuals) revealed the cysteine to tyrosine substitution at amino acid residue 282 (C282Y) in the protein. Surprisingly, matching samples from one patient with a heterozygous C282Y mutation in the germline, showed loss of heterozygosity in the tumor sample at the mutant HFE allele resulting in loss of the C282Y and retention of the normal allele. In addition, we examined 45 tumor cell lines from 11 different tissues. Five cell lines had a heterozygous mutation of HFE, none had a homozygous HFE mutation in the coding region. In summary, our experiments suggest that HFE mutations are not associated with a growth advantage for cancer cells.
Müller
Claudia I
CI
Division of Hematology/Oncology, Davis 5065, Cedars-Sinai Medical Center, UCLA School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. mullerci@cshs.org
Miller
Carl W
CW
Kawabata
Hiroshi
H
McKenna
Robert J
RJ
Marchevsky
Alberto M
AM
Koeffler
H Phillip
HP
D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D045325:HCT116 Cells; D018922:HL-60 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D009154:Mutation; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational
D004273:DNA, Neoplasm; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron