mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma

Rebecca Sowers, Junya Toguchida, Jing Qin, Paul A. Meyers, John H. Healey, Andrew Huvos, Debabrata Banerjee, Joseph R. Bertino, Richard Gorlick

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Previous studies have shown that decreased expression of the reduced folate carrier (RFC) and increased expression of dihydrofolate reductase (DHFR) are associated with intrinsic and acquired methotrexate resistance, respectively, in osteosarcoma (OS). It has also been shown in colorectal cancer that E2F-1 expression correlates with thymidylate synthase (TS) and, to a lesser extent, DHFR expression. To begin to investigate the regulation of DHFR and RFC expression in OS samples, mRNA expression of E2F-1 and E2F-4 were measured in OS tumor samples and related to DHFR, RFC, and TS mRNA expression. Using fluorescent quantitative real-time PCR, 112 human OS patient samples were investigated for potential E2F-1/E2F-4:DHFR, E2F-1/E2F-4:RFC, and E2F-1/E2F-4:TS correlations. The expression ranges for each gene are as follows: DHFR, 0.02-33.13 (median = 0.20); RFC, 0.02-229.13 (median = 1.91); TS, 0.01-9.99 (median = 0.15); E2F-1, 0.05-69.07 (median = 0.52); and E2F-4, 0.24-52.35 (median = 1.45). Spearman correlation coefficients (rs) for E2F-1:DHFR, E2F-1:RFC, E2F-1:TS, E2F-4:DHFR, E2F-4:RFC, and E2F-4:TS were calculated to be 0.53, 0.63, 0.60, 0.41, 0.58, and 0.33, respectively (P < 0.001). On the basis of this data, moderate correlations exist between E2F-1/E2F-4 and DHFR, RFC, and TS. These results suggest E2F-1/E2F-4 may play a role in the regulation of RFC expression, which has not been reported previously. The E2F transcription factors are also related to DHFR and TS expression in OS samples, suggesting a possible involvement in methotrexate resistance. Although E2F mRNA levels correlate with DHFR, RFC, and TS mRNA expression, additional experiments are necessary to determine the direct effects of these transcription factors and identify other proteins that may influence this relationship.

Original languageEnglish (US)
Pages (from-to)535-541
Number of pages7
JournalMolecular Cancer Therapeutics
Volume2
Issue number6
StatePublished - Jun 2003
Externally publishedYes

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Reduced Folate Carrier Protein
E2F Transcription Factors
Thymidylate Synthase
Tetrahydrofolate Dehydrogenase
Osteosarcoma
Messenger RNA
Methotrexate
Real-Time Polymerase Chain Reaction
Colorectal Neoplasms
Transcription Factors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma. / Sowers, Rebecca; Toguchida, Junya; Qin, Jing; Meyers, Paul A.; Healey, John H.; Huvos, Andrew; Banerjee, Debabrata; Bertino, Joseph R.; Gorlick, Richard.

In: Molecular Cancer Therapeutics, Vol. 2, No. 6, 06.2003, p. 535-541.

Research output: Contribution to journalArticle

Sowers, R, Toguchida, J, Qin, J, Meyers, PA, Healey, JH, Huvos, A, Banerjee, D, Bertino, JR & Gorlick, R 2003, 'mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma', Molecular Cancer Therapeutics, vol. 2, no. 6, pp. 535-541.
Sowers, Rebecca ; Toguchida, Junya ; Qin, Jing ; Meyers, Paul A. ; Healey, John H. ; Huvos, Andrew ; Banerjee, Debabrata ; Bertino, Joseph R. ; Gorlick, Richard. / mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma. In: Molecular Cancer Therapeutics. 2003 ; Vol. 2, No. 6. pp. 535-541.
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abstract = "Previous studies have shown that decreased expression of the reduced folate carrier (RFC) and increased expression of dihydrofolate reductase (DHFR) are associated with intrinsic and acquired methotrexate resistance, respectively, in osteosarcoma (OS). It has also been shown in colorectal cancer that E2F-1 expression correlates with thymidylate synthase (TS) and, to a lesser extent, DHFR expression. To begin to investigate the regulation of DHFR and RFC expression in OS samples, mRNA expression of E2F-1 and E2F-4 were measured in OS tumor samples and related to DHFR, RFC, and TS mRNA expression. Using fluorescent quantitative real-time PCR, 112 human OS patient samples were investigated for potential E2F-1/E2F-4:DHFR, E2F-1/E2F-4:RFC, and E2F-1/E2F-4:TS correlations. The expression ranges for each gene are as follows: DHFR, 0.02-33.13 (median = 0.20); RFC, 0.02-229.13 (median = 1.91); TS, 0.01-9.99 (median = 0.15); E2F-1, 0.05-69.07 (median = 0.52); and E2F-4, 0.24-52.35 (median = 1.45). Spearman correlation coefficients (rs) for E2F-1:DHFR, E2F-1:RFC, E2F-1:TS, E2F-4:DHFR, E2F-4:RFC, and E2F-4:TS were calculated to be 0.53, 0.63, 0.60, 0.41, 0.58, and 0.33, respectively (P < 0.001). On the basis of this data, moderate correlations exist between E2F-1/E2F-4 and DHFR, RFC, and TS. These results suggest E2F-1/E2F-4 may play a role in the regulation of RFC expression, which has not been reported previously. The E2F transcription factors are also related to DHFR and TS expression in OS samples, suggesting a possible involvement in methotrexate resistance. Although E2F mRNA levels correlate with DHFR, RFC, and TS mRNA expression, additional experiments are necessary to determine the direct effects of these transcription factors and identify other proteins that may influence this relationship.",
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T1 - mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma

AU - Sowers, Rebecca

AU - Toguchida, Junya

AU - Qin, Jing

AU - Meyers, Paul A.

AU - Healey, John H.

AU - Huvos, Andrew

AU - Banerjee, Debabrata

AU - Bertino, Joseph R.

AU - Gorlick, Richard

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N2 - Previous studies have shown that decreased expression of the reduced folate carrier (RFC) and increased expression of dihydrofolate reductase (DHFR) are associated with intrinsic and acquired methotrexate resistance, respectively, in osteosarcoma (OS). It has also been shown in colorectal cancer that E2F-1 expression correlates with thymidylate synthase (TS) and, to a lesser extent, DHFR expression. To begin to investigate the regulation of DHFR and RFC expression in OS samples, mRNA expression of E2F-1 and E2F-4 were measured in OS tumor samples and related to DHFR, RFC, and TS mRNA expression. Using fluorescent quantitative real-time PCR, 112 human OS patient samples were investigated for potential E2F-1/E2F-4:DHFR, E2F-1/E2F-4:RFC, and E2F-1/E2F-4:TS correlations. The expression ranges for each gene are as follows: DHFR, 0.02-33.13 (median = 0.20); RFC, 0.02-229.13 (median = 1.91); TS, 0.01-9.99 (median = 0.15); E2F-1, 0.05-69.07 (median = 0.52); and E2F-4, 0.24-52.35 (median = 1.45). Spearman correlation coefficients (rs) for E2F-1:DHFR, E2F-1:RFC, E2F-1:TS, E2F-4:DHFR, E2F-4:RFC, and E2F-4:TS were calculated to be 0.53, 0.63, 0.60, 0.41, 0.58, and 0.33, respectively (P < 0.001). On the basis of this data, moderate correlations exist between E2F-1/E2F-4 and DHFR, RFC, and TS. These results suggest E2F-1/E2F-4 may play a role in the regulation of RFC expression, which has not been reported previously. The E2F transcription factors are also related to DHFR and TS expression in OS samples, suggesting a possible involvement in methotrexate resistance. Although E2F mRNA levels correlate with DHFR, RFC, and TS mRNA expression, additional experiments are necessary to determine the direct effects of these transcription factors and identify other proteins that may influence this relationship.

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