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Integrity of the 1,25-dihydroxyvitamin D3 receptor in bone, lung, and other cancers
C W Miller1, R Morosetti, M J Campbell
1Division of Hematology/Oncology, Cedars-Sinai Research Institute, University of California at Los Angeles School of Medicine 90048, USA.
Abstract:
Differentiation and proliferation can be regulated in diverse cell types by 1,25-dihydroxyvitamin D3. These effects derive from modulation of gene expression mediated by the interaction of 1,25-dihydroxyvitamin D3 with the vitamin D receptor (VDR). The VDR is one of the nuclear hormone receptors. Because these transcription factors play a key role in growth control, some nuclear hormone receptors, such as the retinoic acid receptor alpha, can be disrupted in cancer. With these alterations in mind, we looked for alterations of the VDR gene in a variety of cancers, including 68 osteosarcomas, 23 other sarcomas, 34 non-small cell lung cancers, and 44 cell lines representing many tumor types. Gross integrity of the VDR gene was examined on Southern blots probed with the coding region of the VDR cDNA. The presence of point mutations targeting VDR exons 2-7 was assessed by polymerase chain reaction-single-strand conformation polymorphism analysis and direct DNA sequencing. Two alterations were detected; direct DNA sequencing of these samples revealed one silent mutation in codon 79 and a base change in intron 3. These results suggest that mutations and rearrangement of the VDR do not play a role in the cancers studied.
Insights
Mutations in the vitamin D receptor (VDR) gene are not a significant factor in the development of various cancers. This study found minimal VDR gene alterations in osteosarcomas, sarcomas, and lung cancers.
Area of Science:
- Molecular Biology
- Oncology
- Endocrinology
Background:
- 1,25-dihydroxyvitamin D3 regulates cell differentiation and proliferation by modulating gene expression via the vitamin D receptor (VDR).
- The VDR, a nuclear hormone receptor, plays a crucial role in growth control.
- Alterations in nuclear hormone receptors are implicated in cancer development.
Purpose of the Study:
- To investigate alterations in the VDR gene in various cancer types.
- To determine if VDR gene mutations or rearrangements contribute to cancer pathogenesis.
Main Methods:
- Southern blot analysis was used to assess the gross integrity of the VDR gene.
- Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct DNA sequencing were employed to detect point mutations in VDR exons 2-7.
- Analysis included 68 osteosarcomas, 23 other sarcomas, 34 non-small cell lung cancers, and 44 diverse cancer cell lines.
Main Results:
- Two VDR gene alterations were detected among the studied samples.
- These included one silent mutation at codon 79 and a base change in intron 3.
- No significant mutations or rearrangements of the VDR gene were identified in the majority of the cancers examined.
Conclusions:
- The VDR gene does not appear to be frequently mutated or rearranged in the studied osteosarcomas, sarcomas, and non-small cell lung cancers.
- These findings suggest that VDR gene alterations are unlikely to be a major driver in the pathogenesis of these cancers.