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Expression of VDR and CYP24A1 mRNA in human tumors
Mark G Anderson1, Masaki Nakane, Xiaoan Ruan
1Abbott Laboratories, R4CM, AP52, 200 Abbott Park Rd., Abbott Park, IL 60064, USA.
Abstract:
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its analogues have been shown to inhibit proliferation of human cancer cells mediated by vitamin D receptor (VDR). The over-expression of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1), an enzyme involved in the metabolism of 1,25(OH)2D3 and its analogues, is associated with poor prognosis of some human cancers. In this study, we employed real-time reverse transcription PCR to examine the expression of VDR and CYP24A1 mRNA in a cohort of human breast, lung, colon and ovary tumor samples. We found that CYP24A1 mRNA was significantly up-regulated in colon, ovary and lung tumors, but down-regulated in breast tumor relative to the analogous normal tissues. As a comparison, VDR mRNA was modestly down-regulated in colon, breast and lung tumors, but highly up-regulated in ovarian tumors. Treatment of two breast cancer cell lines, SW-620 and MCF-7, and one colon cancer cell line, HT-29, by 1,25(OH)2D3 for 48 h profoundly stimulated CYP24A1 mRNA expression (EC50=0.6, 0.8 and 29.5 nM in SW-620, HT-29 and MCF-7, respectively), but did not significantly affect VDR mRNA expression. Growth as assessed by DNA synthesis was modestly arrested by 1,25(OH)2D3 after 72 h of incubation, but was not altered after a 5-day incubation period. These data suggest that the VDR signaling pathway may be compromised via the modulation of CYP24A1 and VDR in human tumors.
Insights
Vitamin D receptor (VDR) and CYP24A1 gene expression vary in human tumors. This suggests the VDR signaling pathway may be compromised in cancer, impacting treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its analogues inhibit cancer cell proliferation via the vitamin D receptor (VDR).
- Overexpression of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1), involved in 1,25(OH)2D3 metabolism, is linked to poor cancer prognosis.
Purpose of the Study:
- To investigate the expression of VDR and CYP24A1 mRNA in human breast, lung, colon, and ovarian tumors.
- To explore the impact of 1,25(OH)2D3 on CYP24A1 and VDR mRNA expression and cancer cell growth in vitro.
Main Methods:
- Real-time reverse transcription PCR was used to analyze VDR and CYP24A1 mRNA levels in tumor and normal tissue samples.
- Human cancer cell lines (SW-620, MCF-7, HT-29) were treated with 1,25(OH)2D3 to assess gene expression and DNA synthesis.
Main Results:
- CYP24A1 mRNA was significantly upregulated in colon, ovarian, and lung tumors, but downregulated in breast tumors compared to normal tissues.
- VDR mRNA was downregulated in colon, breast, and lung tumors, but highly upregulated in ovarian tumors.
- 1,25(OH)2D3 treatment stimulated CYP24A1 mRNA expression in cancer cell lines and modestly arrested growth via DNA synthesis inhibition.
Conclusions:
- Tumor-specific alterations in CYP24A1 and VDR mRNA expression suggest a compromised VDR signaling pathway in human cancers.
- The differential expression patterns indicate potential roles for VDR and CYP24A1 in cancer development and progression across different tumor types.