ABSTRACT
The vitamin D receptor (VDR) is a transcription factor that mediates a variety of biological functions of 1,25-dihydroxyvitamin D3. Although there is growing evidence of cytological and animal studies supporting the suppressive role of VDR in cancers, the conclusion is still controversial in human cancers and no systematic pan-cancer analysis of VDR is available. We explored the relationships between VDR expression and prognosis, immune infiltration, tumor microenvironment, or gene set enrichment analysis (GSEA) in 33 types of human cancers based on multiple public databases and R software. Meanwhile, the expression and role of VDR were experimentally validated in papillary thyroid cancer (PTC). VDR expression decreased in 8 types and increased in 12 types of cancer compared with normal tissues. Increased expression of VDR was associated with either good or poor prognosis in 13 cancer types. VDR expression was positively correlated with the infiltration of cancer-associated fibroblasts, macrophages, or neutrophils in 20, 12, and 10 cancer types respectively and this correlation was experimentally validated in PTC. Increased VDR expression was associated with increased percentage of stromal or immune components in tumor microenvironment (TME) in 24 cancer types. VDR positively and negatively correlated genes were enriched in immune cell function and energy metabolism pathways, respectively, in the top 9 highly lethal tumors. Additionally, VDR expression was increased in PTC and inhibited cell proliferation and migration. In conclusion, VDR is a potential prognostic biomarker and positively correlated with immune infiltration as well as stromal or immune components in TME in multiple human cancers.
Subject(s)
Biomarkers, Tumor , Gene Expression Regulation, Neoplastic , Receptors, Calcitriol , Thyroid Cancer, Papillary , Tumor Microenvironment , Receptors, Calcitriol/genetics , Receptors, Calcitriol/metabolism , Humans , Tumor Microenvironment/immunology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Prognosis , Thyroid Cancer, Papillary/immunology , Thyroid Cancer, Papillary/genetics , Thyroid Cancer, Papillary/pathology , Thyroid Cancer, Papillary/metabolism , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism , Thyroid Neoplasms/immunology , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Thyroid Neoplasms/metabolism , Neoplasms/immunology , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Cell Line, Tumor , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/immunology , Cancer-Associated Fibroblasts/pathology , Databases, GeneticABSTRACT
Background: Elderly people are at high risk of falls due to decreased muscle strength. So far, there is currently no officially approved medication for treating muscle strength loss. The active vitamin D analogues are promising but inconsistent results have been reported in previous studies. The present study was to meta-analyze the effect of active vitamin D analogues on muscle strength and falls in elderly people. Methods: The protocol was registered with PROSPERO (record number: CRD42021266978). We searched two databases including PubMed and Cochrane Library up until August 2023. Risk ratio (RR) and standardized mean difference (SMD) with 95% confidence intervals (95% CI) were used to assess the effects of active vitamin D analogues on muscle strength or falls. Results: Regarding the effects of calcitriol (n= 1), alfacalcidol (n= 1) and eldecalcitol (n= 1) on falls, all included randomized controlled trials (RCT) recruited 771 participants. Regarding the effects of the effects of calcitriol (n= 4), alfacalcidol (n= 3) and eldecalcitol (n= 3) on muscle strength, all included RCTs recruited 2431 participants. The results showed that in the pooled analysis of three active vitamin D analogues, active vitamin D analogues reduced the risk of fall by 19%. Due to a lack of sufficient data, no separate subgroup analysis was conducted on the effect of each active vitamin D analogue on falls. In the pooled and separate analysis of active vitamin D analogues, no significant effects were found on global muscle, hand grip, and back extensor strength. However, a significant enhancement of quadriceps strength was observed in the pooled analysis and separate analysis of alfacalcidol and eldecalcitol. The separate subgroup analysis on the impact of calcitriol on the quadriceps strength was not performed due to the lack to sufficient data. The results of pooled and separate subgroup analysis of active vitamin D analogues with or without calcium supplementation showed that calcium supplementation did not affect the effect of vitamin D on muscle strength. Conclusions: The use of active vitamin D analogues does not improve global muscle, hand grip, and back extensor strength but improves quadriceps strength and reduces risk of falls in elderly population.
