Polymorphisms and Methylation of the Reduced Folate Carrier in Osteosarcoma

Overview

Journal Clin Orthop Relat Res

Publisher Wolters Kluwer

Specialty Orthopedics

Date 2008 Jun 6

PMID 18528741

Citations 7

Authors

Rui Yang

Jing Qin

Bang H Hoang

John H Healey

Richard Gorlick

Affiliations

Soon will be listed here.

Abstract

High-dose methotrexate is a standard component in the treatment of osteogenic sarcoma. Impaired methotrexate uptake associated with decreased reduced folate carrier expression is a common mechanism of methotrexate resistance in osteogenic sarcoma samples. We investigated whether promoter methylation and polymorphisms in the 3' untranslated region are involved in regulating reduced folate carrier expression. In a cohort of 66 osteogenic sarcoma specimens, quantitative methylation-specific polymerase chain reaction and single-strand conformation polymorphism were performed. We found detectable levels of promoter methylation in 84.3% of samples. When related to the reduced folate carrier mRNA levels, a trend was observed that reduced folate carrier expression is lower in samples (median, 0.7) with greater than 10% DNA methylation as compared with those (median, 2.3) with less than 10% DNA methylation. The heterozygous polymorphisms of 2582 T/G and 2617C/T in the 3' untranslated region showed reduced folate carrier expression (median, 0.9) as compared with the wild-type 2582T and 2617C (median, 4.2). The data suggest promoter methylation and polymorphisms in the 3' untranslated region of the reduced folate carrier may be involved in its transcriptional regulation in osteogenic sarcoma. Further study is required to confirm this finding.

Citing Articles

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A summary of the osteosarcoma banking efforts: a report from the Children's Oncology Group and the QuadW Foundation.

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References

Jones P, Baylin S . The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3(6):415-28. DOI: 10.1038/nrg816. View

Ferreri A, DellOro S, Capello D, Ponzoni M, Iuzzolino P, Rossi D . Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas. Br J Haematol. 2004; 126(5):657-64. DOI: 10.1111/j.1365-2141.2004.05109.x. View

Tolner B, Roy K, Sirotnak F . Structural analysis of the human RFC-1 gene encoding a folate transporter reveals multiple promoters and alternatively spliced transcripts with 5' end heterogeneity. Gene. 1998; 211(2):331-41. DOI: 10.1016/s0378-1119(98)00123-1. View

Banerjee D, Mayer-Kuckuk P, Capiaux G, Budak-Alpdogan T, Gorlick R, Bertino J . Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. Biochim Biophys Acta. 2002; 1587(2-3):164-73. DOI: 10.1016/s0925-4439(02)00079-0. View

Nataraj A, Kusukawa N, Highsmith Jr W . Single-strand conformation polymorphism and heteroduplex analysis for gel-based mutation detection. Electrophoresis. 1999; 20(6):1177-85. DOI: 10.1002/(SICI)1522-2683(19990101)20:6<1177::AID-ELPS1177>3.0.CO;2-2. View

Worm J, Kirkin A, Dzhandzhugazyan K, Guldberg P . Methylation-dependent silencing of the reduced folate carrier gene in inherently methotrexate-resistant human breast cancer cells. J Biol Chem. 2001; 276(43):39990-40000. DOI: 10.1074/jbc.M103181200. View

Wong S, Proefke S, Bhushan A, Matherly L . Isolation of human cDNAs that restore methotrexate sensitivity and reduced folate carrier activity in methotrexate transport-defective Chinese hamster ovary cells. J Biol Chem. 1995; 270(29):17468-75. DOI: 10.1074/jbc.270.29.17468. View

Meyers P, Gorlick R, Heller G, Casper E, Lane J, Huvos A . Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J Clin Oncol. 1998; 16(7):2452-8. DOI: 10.1200/JCO.1998.16.7.2452. View

Williams F, Flintoff W . Isolation of a human cDNA that complements a mutant hamster cell defective in methotrexate uptake. J Biol Chem. 1995; 270(7):2987-92. DOI: 10.1074/jbc.270.7.2987. View

10.

Day D, Tuite M . Post-transcriptional gene regulatory mechanisms in eukaryotes: an overview. J Endocrinol. 1998; 157(3):361-71. DOI: 10.1677/joe.0.1570361. View

11.

Zhang L, Wong S, Matherly L . Transcript heterogeneity of the human reduced folate carrier results from the use of multiple promoters and variable splicing of alternative upstream exons. Biochem J. 1998; 332 ( Pt 3):773-80. PMC: 1219540. DOI: 10.1042/bj3320773. View

12.

Mintz M, Sowers R, Brown K, Hilmer S, Mazza B, Huvos A . An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. Cancer Res. 2005; 65(5):1748-54. DOI: 10.1158/0008-5472.CAN-04-2463. View

13.

Prasad P, Ramamoorthy S, Leibach F, Ganapathy V . Molecular cloning of the human placental folate transporter. Biochem Biophys Res Commun. 1995; 206(2):681-7. DOI: 10.1006/bbrc.1995.1096. View

14.

Gong M, Cowan K, Gudas J, Moscow J . Isolation and characterization of genomic sequences involved in the regulation of the human reduced folate carrier gene (RFC1). Gene. 1999; 233(1-2):21-31. DOI: 10.1016/s0378-1119(99)00166-3. View

15.

Whetstine J, Flatley R, Matherly L . The human reduced folate carrier gene is ubiquitously and differentially expressed in normal human tissues: identification of seven non-coding exons and characterization of a novel promoter. Biochem J. 2002; 367(Pt 3):629-40. PMC: 1222932. DOI: 10.1042/BJ20020512. View

16.

Matherly L, Goldman D . Membrane transport of folates. Vitam Horm. 2003; 66:403-56. DOI: 10.1016/s0083-6729(03)01012-4. View

17.

Williams F, Flintoff W . Structural organization of the human reduced folate carrier gene: evidence for 5' heterogeneity in lymphoblast mRNA. Somat Cell Mol Genet. 1999; 24(3):143-56. DOI: 10.1023/b:scam.0000007117.50428.63. View

18.

Moscow J, Gong M, He R, Sgagias M, Dixon K, Anzick S . Isolation of a gene encoding a human reduced folate carrier (RFC1) and analysis of its expression in transport-deficient, methotrexate-resistant human breast cancer cells. Cancer Res. 1995; 55(17):3790-4. View

19.

Zhao R, Goldman I . Resistance to antifolates. Oncogene. 2003; 22(47):7431-57. DOI: 10.1038/sj.onc.1206946. View

20.

Goto Y, Yue L, Yokoi A, Nishimura R, Uehara T, Koizumi S . A novel single-nucleotide polymorphism in the 3'-untranslated region of the human dihydrofolate reductase gene with enhanced expression. Clin Cancer Res. 2001; 7(7):1952-6. View