BACKGROUND/AIM: Vitamin D analogs have a protective effect on carcinogenesis in humans. Since vitamin D receptor (VDR) is detected in many histotypes of cancer, this study evaluated the role of VDR expression in endometrioid carcinoma.
MATERIALS AND METHODS: Tumor samples were collected from 60 patients who had undergone surgery, and the pattern of VDR expression assessed in tissue microarray (TMA) blocks of tumor samples. When VDR expression in the cytoplasm was higher than that in the nucleus, this was noted as 'displacement'. Using statistical analysis, the relationship between VDR expression and clinicopathological factors was evaluated.
RESULTS: Immunohistochemical staining of nuclear VDR was as follows: Negative: 32 (53.3%); mild: 13 (21.7%); moderate: 14 (23.3%); strong: 1 (1.7%). For cytoplasmic VDR expression: Negative: 2 (3.3%); mild: 19 (31.7%); moderate: 31 (51.7%); strong: 7 (11.7%). VDR displacement was found in 42 (70%) cores. VDR displacement was significantly positively correlated with endometrioid carcinoma having lower histological grade (1, p=0.03).
CONCLUSION: Displacement of VDR was significantly correlated with lower histological grade. Clinicians might be able to predict prognosis and decide therapies related to vitamin D analogs using this remarkable biomarker for endometrial carcinoma.

Scientific evidence linking vitamin D with various cancer types is growing, but the effects of vitamin D on ovarian cancer stem cell‑like cells (CSCs) are largely unknown. The present study aimed to examine whether vitamin D was able to restrain the stemness of ovarian cancer. A side population (SP) from malignant ovarian surface epithelial cells was identified as CSCs, in vitro and in vivo. Furthermore, 1α,25‑dihydroxyvitamin D3 [1α,25(OH)2D3] treatment inhibited the self‑renewal capacity of SP cells by decreasing the sphere formation rate and by suppressing the mRNA expression levels of cluster of differentiation CD44, NANOG, OCT4, SOX2, Krüppel‑like factor 4 and adenosine triphosphate binding cassette subfamily G member 2. Additionally, 1α,25(OH)2D3 treatment decreased the expression of Cyclin D1, whereas it increased the expression of β‑catenin and vitamin D receptor (VDR). Notably, immunofluorescence staining verified that 1α,25(OH)2D3 promoted the expression of β‑catenin in the cytoplasm. Furthermore, vitamin D3 delayed the onset of tumor formation derived from injection of ovarian CSCs to nude mice, by reducing CD44 and enhancing β‑catenin expressions in vivo. In conclusion, 1α,25(OH)2D3 restrains the stem cell‑like properties of ovarian cancer cells by enhancing the expression of VDR, by promoting the expression of β‑catenin in the cytoplasm, and by suppressing the expression of CD44. These findings provide a novel insight into the functions of vitamin D in diminishing the stemness of cancer CSCs.

OBJECTIVE: Vitamin D receptor (VDR) activities have been noted for a number of B cell malignancies which showed varying sensitivities to vitamin D3 (1,25-dihydroxyvitamin D3, VD3, calcitriol) and its synthetic analogs. The objective of this study was to address the potential effects of VD3 and vitamin D3 analogs (VDAs) on the growth of Hodgkin's lymphoma (HL), a malignant pathology of B cell origin, in vitro.
RESULTS: Immunofluorescence staining showed the expression of VDR by primary Hodgkin's (H) and Reed-Sternberg (RS)-HRS-tumor cells in HL histological sections. Western blot analyses revealed expression of VDR in the HL cell lines Hs445, HDLM2, KMH2, and L428. One-way analysis of variance (ANOVA) on data obtained from water-soluble tetrazolium 1 (WST-1) cell proliferation assay showed decreased cell growth in HDLM2 and L428, 72 h after treatment with 10 µM of either VD3 of VDAs. Western blot analyses showed that treatment of L428 cells with the VDAs (calcipotriol and EB1089) resulted in modest increases in nuclear accumulation of VDR (nuVDR) compared to either dimethyl sulfoxide (DMSO) or VD3 treatments. nuVDR for DMSO control and VD3 was comparable. These results suggest that VD3 or VDAs may affect growth of HL.

OBJECTIVES: The role of p62 in cancer is controversial. Evidence has shown that p62 is upregulated in different cancers and promotes tumour growth, such as in liver cancer and lung cancer. However, a recent study showed that the downregulation of p62 in hepatic stellate cells (HSCs) promotes hepatocellular carcinoma (HCC) development. How p62 is regulated in colorectal cancer (CRC) remains largely unknown. In this study, we aimed to investigate the roles and molecular mechanisms of p62 in CRC.
MATERIALS AND METHODS: The expression levels of p62 in CRC tissues and adjacent non-tumour tissues were determined by immunohistochemistry (IHC). Stable p62-overexpression HCT116 cells and p62-knockdown SW480 cells were established with lentiviral vectors. The role of p62 in CRC was investigated in in vitro and in vivo functional studies. The relationship between p62 and the vitamin D receptor (VDR) was investigated by coimmunoprecipitation (Co-IP) assays.
RESULTS: p62 was significantly upregulated in CRC, and a high p62 level was an independent risk factor for a poor prognosis in CRC patients. p62 promoted CRC migration and invasion by inhibiting apoptosis and promoting cell proliferation in vitro, and p62 aggravated tumour growth and metastasis in vivo. Co-IP assays indicated that p62 interacts with the VDR and may target the NRF2-NQO1 axis.
CONCLUSIONS: Our study suggested that p62 functions as an oncogene in CRC through inhibiting apoptosis and promoting cell proliferation by interacting with the VDR.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-age women. Multiple susceptible gene as well as environmental factors and their interaction each other are contributed to the PCOS risk. Several case-control studies have researched the associations of the vitamin D receptor gene (VDR) polymorphisms with PCOS susceptibility, but the jury is still out. Here, we carried out a meta-analysis to clarify polymorphisms between ApaI (C/A) (rs7975232), BsmI (G/A) (rs1544410), FokI (C/T) (rs10735810), TaqI (T/C) (rs731236) and Tru9I (G/A) (rs757343) in the VDR gene and PCOS susceptibility based on relative lager sample size.
METHODS: English database of PubMed and Embase, and Chinese database of Wanfang and China National Knowledge Infrastructure (CNKI) databases were retrivaled for the relationship between VDR gene variates and PCOS susceptibility published before 31th, May 2018. Crude odds ratios (ORs) and its 95% confidence intervals (95% CIs) in different comparisons were used to detected the strength of the association. All the statistical analyses of the present meta-analysis were performed by STATA version 12.0 software.
RESULTS: Totally, 3587 (PCOS group 1922; control group 1665) participants from 13 studies were included which met our inclusion criteria. A statistically significant association between VDR ApaI (rs7975232) polymorphism and PCOS susceptibility (C vs. A: OR = 1.19, 95%CI = 1.06~1.34, P = 0.004) was found in the overall population. After stratified by ethnicity, we showed that there is a significant association between VDR ApaI (rs7975232) polymorphism and susceptibility to PCOS in the Asian (C vs. A: OR = 1.21, 95%CI = 1.04~1.42, P = 0.016) population, but this association was not found in the Caucasian population. Additionally, a significant relationship between VDR BsmI (rs1544410) variates with PCOS susceptibility in the Asian (G vs. A: OR = 1.27, 95%CI = 1.06~1.53, P = 0.011) population, but this association was not found in the Caucasian population. We didn't find any association between VDR FokI (rs2228570), VDR TaqI (rs731236), VDR Tru9I (rs757343) and PCOS susceptibility in the overall and the subgroup populations.
CONCLUSIONS: Our findings demonstrated that VDR ApaI (rs7975232) and VDR BsmI (rs1544410) polymorphisms are correlated with susceptibility to PCOS in the Asian population and VDR TaqI (rs731236), VDR FokI (rs2228570), VDR Tru9I (rs757343) did not reveal a relationship with the PCOS susceptibility.

Emerging evidence associates vitamin D deficiency and vitamin D receptor (

The association between vitamin D receptor (VDR) genetic polymorphism and lung cancer risk has been evaluated by the previous meta-analyses. Due to the emergence of novel studies and inappropriate inclusion of overlapping populations, an updated meta-analysis on recent evidences is necessarily needed. We comprehensively searched databases of PubMed, Web of Science and Chinese National Knowledge Infrastructure and finally obtained 7 eligible studies according to the inclusion criteria. Four positions on VDR gene, namely ApaI (rs7975232), BsmI (rs1544410), FokI (rs10735810) and TaqI (rs731236), were considered in this investigation. Data pooling found no significant association of lung cancer risk with ApaI or FokI. In contrast, it was indicated that the BsmI A allele was negatively related to the lung cancer risk, compared with the G allele (OR = 0.51, 95% CI = 0.33-0.79). Individuals with BsmI AA (OR = 0.53, 95% CI = 0.26-1.11) and AG genotypes (OR = 0.46, 95% CI = 0.30-0.71) showed decreased risk of lung cancer, compared with those of GG genotype. Regarding the TaqI polymorphism, the T allele carriers were at increased risk of lung cancer (OR = 1.25, 95% CI = 1.04-1.50). Compared with the TaqI TC+CC genotype, the TT genotype was positively associated with lung cancer risk (OR = 1.42, 95% CI = 1.11-1.82). No publication bias was identified in any of the analysis. In conclusion, VDR genetic polymorphism may be correlated to lung cancer risk. Given limited number of the included studies, more observations are warranted to draw a safer conclusion.

Breast cancer is the leading cause of death among women worldwide. It is a multi-factorial disease caused by genetic and environmental factors. Vitamin D has been hypothesized to lower the risk of breast cancer via the nuclear vitamin D receptor (VDR). Genetic variants of these vitamin D metabolizing genes may alter the bioavailability of vitamin D, and hence modulate the risk of breast cancer. Materials and Methods: The distribution of Fok1 VDR gene (rs2228570) polymorphism and its association with breast cancer was analysed in a case–control study based on 125 breast cancer patients and 125 healthy females from North Indian population, using PCR-RFLP. An In silico exploration of the probable mechanism of increased risk of breast cancer was performed to investigate the role of single nucleotide polymorphisms (SNPs) in cancer susceptibility. Results: The Fok1 ff genotype was significantly associated with an increased risk of breast cancer (p=0.001; χ2=13.09; OR=16.909; %95 CI=2.20 - 130.11). In silico analysis indicated that SNPs may lead to a loss in affinity of VDR to calcitriol, and may also cause the impairment of normal interaction of liganded VDR with its heterodimeric partner, the retinoid X receptor (RXR), at protein level, thereby affecting target gene transcription. Conclusion: Breast cancer risk and pathogenesis in females can be influenced by SNPs. SNPs in VDR may cause alterations in the major molecular actions of VDR, namely ligand binding, heterodimerization and transactivation. VDRE binding and co-activator recruitment by VDR appear to be functionally inseparable events that affect vitamin D-elicited gene transcription. This indicates that breast cancer risk and pathogenesis in females may be influenced by SNPs.

BACKGROUND: Emerging evidence from pre-clinical and clinical studies has shown that vitamin D (VD) plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). Potentially functional ApaI polymorphism of vitamin D receptor (VDR) gene has been implicated in PCOS risk, but individually published studies have yielded inconclusive results.
OBJECTIVES: Studies on the associations of VDR gene polymorphisms with PCOS susceptibility reported conflicting results. The objective of this study was to perform a systematic meta-analysis to clarify this issue.
MATERIAL AND METHODS: We searched for all publications regarding the associations mentioned above in PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI) databases updated up to April 2017. A meta-analysis of the overall odds ratios (ORs) with 95% confidence interval (CI) was calculated with the fixed or random effect model.
RESULTS: A total of 7 studies fulfilling the inclusion criteria were included in this meta-analysis (1,350 cases and 960 controls). Pooled ORs showed a significant association between ApaI polymorphism and PCOS risk in all 4 genetic models. Subgroup analysis by ethnicity showed that ApaI polymorphism was associated with the risk of PCOS in Asians (aa vs AA: OR = 1.54, 95% CI = 1.04-2.28, p = 0.03). However, ApaI polymorphism (a vs A: OR = 1.34, 95% CI = 1.00-1.79, p = 0.02; aa+Aa vs AA: OR = 1.36, 95% CI = 1.04-1.79, p = 0.03) was associated with the risk of PCOS in Caucasians.
CONCLUSIONS: Our meta-analysis demonstrated that PCOS risk was significantly associated with VDR gene ApaI polymorphism. However, due to the relatively small sample size in this meta-analysis, further studies with a larger sample size should be conducted to confirm the findings.

Alternative splicing modulates gene function by creating splice variants with alternate functions or non-coding RNA activity. Naturally occurring variants of nuclear receptor (NR) genes with dominant negative or gain-of-function phenotypes have been documented, but their cellular roles, regulation, and responsiveness to environmental stress or disease remain unevaluated. Informed by observations that class I androgen and estrogen receptor variants display ligand-independent signaling in human cancer tissues, we questioned whether the function of class II NRs, like the vitamin D receptor (VDR), would also respond to alternative splicing regulation. Artificial VDR constructs lacking exon 3 (Dex3-VDR), encoding part of the DNA binding domain (DBD), and exon 8 (Dex8-VDR), encoding part of the ligand binding domain (LBD), were transiently transfected into DU-145 cells and stably-integrated into Caco-2 cells to study their effect on gene expression and cell viability. Changes in VDR promoter signaling were monitored by the expression of target genes (e.g. CYP24A1, CYP3A4 and CYP3A5). Ligand-independent VDR signaling was observed in variants lacking exon 8, and a significant loss of gene suppressor function was documented for variants lacking exon 3. The gain-of-function behavior of the Dex8-VDR variant was recapitulated in vitro using antisense oligonucleotides (ASO) that induce the skipping of exon 8 in wild-type VDR. ASO targeting the splice acceptor site of exon 8 significantly stimulated ligand-independent VDR reporter activity and the induction of CYP24A1 above controls. These results demonstrate how alternative splicing can re-program NR gene function, highlighting novel mechanisms of toxicity and new opportunities for the use of splice-switching oligonucleotides (SSO) in precision medicine.

Acute myeloid leukemia (AML) is one of the deadliest hematological malignancies without effective treatment for most patients. Vitamin D derivatives (VDDs) - active metabolites 1α,25-dihydroxyvitamin D

MiR-125b belongs to the class of microRNAs, which are short endogenous non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. Recently, it was reported that miR-125b was found to promote migration and invasion of MCF-7 cells and was involved in chemotherapeutic resistance. Decreasing miR-125b expression would have potential therapeutic significance in preventing dissemination of breast cancer cells. The objective of this study was to evaluate miR-125b expression levels in MCF-7 cells following treatment with 1,25-dihydroxyvitamin D

This is the first study to investigate the effect of vitamin D receptor ( VDR) gene single-nucleotide polymorphisms on the clinicopathologic features of papillary thyroid cancer in Turkey. A total of 165 patients with papillary thyroid cancer and 172 controls were included in this case-control study. VDR gene single-nucleotide polymorphisms FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) were evaluated using reverse-transcription polymerase chain reaction. VDR gene polymorphisms BsmI, ApaI, and TaqI did not differ between the papillary thyroid cancer group and control group (p > 0.05, each). BsmI, ApaI, and TaqI were not associated with papillary thyroid cancer risk. The VDR gene FokI CT/TT genotype was associated with an increased papillary thyroid cancer risk (CT vs CC: odds ratio = 1.71, 95% confidence interval = 1.15-2.76, p = 0.028; TT vs CC: odds ratio = 2.44, 95% confidence interval = 1.29-4.62, p = 0.005; CT/TT vs CC: odds ratio = 1.88, 95% confidence interval = 1.20-2.96, p = 0.006; CT/CC vs TT: odds ratio = 1.80, 95% confidence interval = 1.05-3.20, p = 0.041). VDR gene polymorphisms were not in linkage disequilibrium. The FokI TT genotype was associated with having T3 and T4, stage III/IV, extra-thyroidal invasion. The FokI CT/TT or TT genotype was associated with developing N1 status, multifocality, tumor size ≥10 mm, and treatment with radioiodine therapy. Persistence/recurrence did not differ between the FokI genotypes. Carriers of the FokI T allele were at an increased risk of more advanced tumor-node-metastasis stage, greater tumor size, multifocality, and extra-thyroidal invasion of papillary thyroid cancer compared with the CC genotype. VDR gene FokI T allele and TT genotype correlated with aggressiveness of papillary thyroid cancer; thus, FokI could be useful as a poor prognostic factor to assess the high risk of papillary thyroid cancer.

Oral cancer is known as one of the most common cancers, with a poor prognosis, related to delayed clinical diagnosis, either due to the lack of particular biomarkers related to the disease or costly therapeutic alternatives. Vitamin D executes its functions by interacting with the vitamin D receptor (VDR), both in healthy and diseased individuals, including oral cancer. This review discusses the role of vitamin D and VDR on tumorigenesis, emphasizing on oral cancer. Furthermore, regulation of VDR expression, mechanisms of anticancer effects of calcitriol, oral cancer chemoresistance and its relation with VDR and polymorphisms of VDR gene will be discussed. The manuscript is prepared mainly using the information collected from PubMed and MEDLINE.

Prostate cancer (PC) is the most common cancer among men worldwide and its pathogenesis is complex. The development of PC depends on family and environmental factors. Vitamin D can be associated with both of these factors. Its reduced serum concentration has been reported in a number of tumors. However, in the case of PC, the study results are conflicting. Polymorphism of VDR gene may also be involved in the development of this cancer. The aim of the study was to compare the frequency of selected polymorphisms in patients with PC and in men without this disease. Seventy-two Caucasian males aged 35-75 years with histologically proven PC (T1/T2) were enrolled in the study group. Seventy-two random age-matched Caucasian out-patient subjects formed the control group. VDR (FokI, BsmI and TaqI) gene polymorphism (rs2228570, rs1544410, rs731236) was determined by TaqMan® SNP Genotyping. The Hardy-Weinberg Equilibrium (HWE) - p> 0.05 was in all studied polymorphisms. Deviations from the HWE were not found. There were no differences between the study group and the control group. No difference was found when the groups were compared in terms of age or the Gleason score.

Vitamin D and its receptor may play a role in preventing tumor development and progression. As such antineoplastic effects are expected to be weak and to act over long periods, conditions with increased tumor incidence, such as the neurofibromatosis type 1 (NF1), provide suitable study models. We previously found an inverse correlation of serum 25(OH)D concentration with number of neurofibromas in NF1. Here we aim to further explore the role of the vitamin D receptor. A total of 141 adult NF1 patients were included in the study. For 101 of them, serum vitamin 25(OH)D data were available. From 87 patients, blood samples were obtained in PaxGene tubes containing a reagent to stabilize RNA immediately. mRNA of the vitamin D receptor (VDR) gene (coding for the vitamin D receptor) was measured by means of RT-PCR. Correlation of laboratory data with NF1-related tumors was statistically evaluated. Vitamin D receptor in NF1-tumors was examined by means of immunohistochemistry using an antibody against the vitamin D1 receptor. The number of dermal neurofibromas was significantly inversely correlated with VDR mRNA level and with serum 25(OH)D concentration in NF1 patients. In contrast, plexiform neurofibroma and malignant peripheral nerve sheath tumor did not correlate with these two parameters. Immunostaining did not detect vitamin D receptor in NF1-tumors. Both vitamin D and its receptor may play a role in suppressing the development of neurofibromas. Sustaining 25(OH)D at an adequate level may contribute to controlling neurofibromas and possibly also other tumors. This is especially important for individuals with lower expression of VDR.

Hepatocellular carcinoma (HCC) accounts for the fifth most common cancer worldwide. Vitamin D and antihistamines have been shown to play an anti-tumor role in various tumors. In the present study, we ought to investigate the synergistic effect of astemizole and Vitamin D in HCC cells. We showed that astemizole enhanced the anti-tumor effect of Vitamin D in HCC both in vitro and in vivo. Astemizole enhanced Vitamin D-induced decrease of cell viability and proliferation, increase of apoptosis, decrease of cell migration and invasion in HCC cells in vitro and decrease of tumor number, mass and incidence in HCC in vivo. Astemizole increased VDR expression both in HCC cells in vitro and in tumor tissues in vivo. Downregulation of VDR significantly inhibited the synergistic effect of Vitamin D and astemizole on HCC cell viability, proliferation, apoptosis, migration and invasion. Bioinformatics analysis identified that miR-125a-5p had a putative binding site in the 3'-UTR of VDR. miR-125a-5p mimics inhibited astemizole-induced increase of VDR and enhancement of the anti-tumor effect of Vitamin D in HCC. Reporter gene assay has confirmed that VDR was regulated by miR-125a-5p. miR-125a-5p inhibitors increased VDR expression and decreased cell viability and proliferation in HCC cells. Moreover, VDR and miR-125a-5p expression in tumor tissues in HCC patients were negatively correlated. We identified that inhibition of miR-125a-5p and subsequent upregulation of VDR was involved in astemizole-induced enhancement of the anti-tumor effect of Vitamin D in HCC. These results highlight the importance of combined treatment of astemizole and Vitamin D and provide novel insights into the role of miR-125a-5p-VDR signaling in HCC.

Objective: In acute lymphoblastic leukemia (ALL), various clinical risk factors and genetic predispositions contribute to the development of bone complications during and after chemotherapy. In this study, we aimed to investigate whether vitamin D receptor (
Materials and Methods: Fifty children with ALL who were treated with the ALL Berlin-Frankfurt-Muenster-95 protocol between 1998 and 2008 and were followed for at least 7 years were enrolled. The control group consisted of 96 healthy children.
Results: Low BMD (16%), osteoporosis (12%), and osteonecrosis (8%) were present in a total of 18 patients (36%). The frequency of osteonecrosis and total bone abnormalities was significantly higher in children aged ≥10 years (p=0.001). The risk of low BMD and osteonecrosis was higher in those with vitamin D deficiency. Only the
Conclusion: The development of therapy-induced bone mineral loss and osteonecrosis in children with ALL is frequent and the risk is especially higher in children aged ≥10 years and with vitamin D deficiency. The association between

Vitamin D is a precursor for secosteroidal hormones, which demonstrate pleiotropic biological activities, including the regulation of growth and the differentiation of normal and malignant cells. Our previous studies have indicated that the inhibition of melanoma proliferation by a short side-chain, low calcemic analog of vitamin D-21(OH)pD is not fully dependent on the expression of vitamin D receptor (VDR). We have examined the effects of classic vitamin D metabolites, 1,25(OH)₂D₃ and 25(OH)D₃, and two low calcemic vitamin D analogs, (21(OH)pD and calcipotriol), on proliferation, mRNA expression and vitamin D receptor (VDR) translocation in three human melanoma cell lines: WM98, A375 and SK-MEL-188b (subline b of SK-MEL-188, which lost responsiveness to 1,25(OH)₂D₃ and became VDR

This study aimed to investigate the association between vitamin D (VitD) levels, polymorphisms in VDR gene (ApaI, BsmI, FokI, and TaqI) and the polycystic ovary syndrome (PCOS) in a group of Brazilian women. A total of 100 patients with PCOS and 100 control women were included. The quantification of 25-hydroxyvitamin D (25(OH)D) was performed in high-performance liquid chromatography (HPLC). Polymorphisms on VDR gene were performed by PCR-RFLP. The BsmI AG genotype was more frequent in PCOS group, while the GG genotype was more frequent in the control group (p = .007). The frequency of the Taql CC genotype was higher in PCOS group, while the CT genotype was the most frequent in the control group (p = .021). Mean serum VitD levels were similar between the groups. However, there was a negative correlation between VitD levels and Ferriman-Gallwey score (p = .031, r = -.260) in the PCOS group. The TaqI and BsmI polymorphisms were associated with PCOS. Moreover, VitD levels are associated with the clinical hyperandrogenism. The data suggest the role of VitD in PCOS development and its complications.

OBJECTIVES: To evaluate tissue concentration of 1, 25 dihydroxyvitamin D3, and gene expression level of CYP27B1 that codes for 1-α hydroxylase (vitamin D activating enzyme), and CYP24A1 that codes for 24-hydroxylase (vitamin D catabolizing enzyme) in human uterine leiomyoma (ULM), its adjacent myometrium (Myo-F), and normal myometrium (Myo-N).
STUDY DESIGN: Levels of 1, 25 dihydroxyvitamin D3 were measured using HPLC and Diode detectors whereas CYP27B1, and CYP24A1 expressions were assessed using Real-Time PCR in ULM, Myo-F, and Myo-N. Non-parametric statistics were used.
RESULTS: ULMs contained significantly less 1, 25 dihydroxy vitamin D3 compared to Myo-F (3.0, IQR: 1.0-9.0 versus 6.0, IQR: 3.0-13.0 μg/ kg, P value is 0.03). No significant difference was detected between ULM and Myo-N, or Myo-F and Myo-N. Intratumoral level of the active form of vitamin D did not differ according to the type of ULM (submucous or interstitial/subserous), or to the ULM volume. CYP27B1 was expressed in ULM (2.17, IQR: 0.65-4.9), Myo-F (4.94, IQR: 1.04-22.59), and Myo-N (0.99, IQR: 0.49-1.71) to a comparable level. CYP24A1 expression was significantly higher in ULM compared to Myo-N (2.00, IQR: 0.69-10.77 versus 0.22, IQR: 00- 0.96, respectively, P value is 0.04).
CONCLUSIONS: Human ULMs contain significantly lower 1, 25 dihydroxyvitamin D3 than its adjacent myometrium. ULM, Myo-F, and Myo-N express CYP27B1 and CYP24A1. ULMs express significantly higher level of CYP24A1 than normal myometrium indicating that over expression of 24-hydroxylase is a mechanism by which ULMs sustain a relative state of hypovitaminosis D.

miR-372/373, a cluster of stem cell-specific microRNAs transactivated by the Wnt pathway, has been reported to be dysregulated in various cancers, particularly colorectal cancer (CRC); however, the unique role of these microRNAs in cancer remains to be discovered. In the present study, we characterized the upregulation in expression of miR-372/373 in CRC tissues from The Cancer Genome Atlas data, and then showed that overexpression of miR-372/373 enhanced the stemness of CRC cells by enriching the CD26/CD24-positive cell population and promoting self-renewal, chemotherapy resistance and the invasive potential of CRC cells. To clarify the mechanism underlying microRNA-induced stemness, we profiled 45 cell signaling pathways in CRC cells overexpressing miR-372/373 and found that stemness-related pathways, such as Nanog and Hedgehog, were upregulated. Instead, differentiation-related pathways, such as NFκB, MAPK/Erk and VDR, were markedly repressed by miR-372/373. Numerous new targets of miR-372/373 were identified, including SPOP, VDR and SETD7, all of which are factors important for cell differentiation. Furthermore, in contrast to the increase in miR-372/373 expression in CRC tissues, the expression levels of SPOP and VDR mRNA were significantly downregulated in these tissues, indicative of the poor differentiation status of CRC. Taken together, our findings suggest that miR-372/373 enhance CRC cell stemness by repressing the expression of differentiation genes. These results provide new insights for understanding the function and mechanisms of stem cell-specific microRNAs in the development of metastasis and drug resistance in CRC.

PURPOSE: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis.
PATIENTS AND METHODS: Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines.
RESULTS: The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70-0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63-0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor.
CONCLUSION: Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients.

BACKGROUND: To identify the most suitable genetic model for detecting the risk of breast cancer (BC)/ovarian cancer (OC) in specific populations.
METHODS: Databases were searched for related studies published up to October 2017. First, VDR genetic polymorphisms were compared in patients with and without cancer. Second, a network meta-analysis was used to reveal the relation between VDR genetic polymorphisms with disease outcomes. Subgroup analyses and a meta-regression were performed according to cancer types, ethnicity and genotypic method. The study is registered in PROSPERO with an ID: CRD42017075505.
RESULTS: Forty-five studies were eligible, which included 65,754 patients and 55 clinical analyses. Of genetic models, results suggested that the recessive model with the CDX2 polymorphism predicted the risk of BC in all cases. The recessive polymorphism model with the rs2228570 (FokI) polymorphism seemed to the best predictor of BC in Caucasian patients, whereas the homozygote model with the CDX2 polymorphism appeared to best predict BC in African-American patients. The homozygote model with the rs2228570 (FokI) polymorphism model appeared to detect the risk of OC in all cases, whereas the heterozygote model with the rs1544410 (BsmI) polymorphism seemed to detect the risk of OC in Caucasian patients.
CONCLUSIONS: By detecting the risk of BC, the recessive model with the rs2228570 (FokI) polymorphism is likely the best genetic model in Caucasian patients, and the homozygote model with the CDX2 polymorphism appears to be best genetic model in African-American patients. Moreover, for detecting clinical risk of OC, heterozygote models with the rs1544410 (BsmI) polymorphism is likely the best genetic model for detecting the risk of OC in Caucasian patients.

BACKGROUND: Vitamin D has anticarcinogenic and immune-related properties and may protect against some diseases, including breast cancer. Vitamin D affects gene transcription and may influence DNA methylation.
METHODS: We studied the relationships between serum vitamin D, DNA methylation, and breast cancer using a case-cohort sample (1070 cases, 1277 in subcohort) of non-Hispanic white women. For our primary analysis, we used robust linear regression to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and methylation within a random sample of the cohort ("subcohort"). We focused on 198 CpGs in or near seven vitamin D-related genes. For these 198 candidate CpG loci, we also examined how multiplicative interactions between methylation and 25(OH)D were associated with breast cancer risk. This was done using Cox proportional hazards models and the full case-cohort sample. We additionally conducted an exploratory epigenome-wide association study (EWAS) of the association between 25(OH)D and DNA methylation in the subcohort.
RESULTS: Of the CpGs in vitamin D-related genes, cg21201924 (RXRA) had the lowest p value for association with 25(OH)D (p = 0.0004). Twenty-two other candidate CpGs were associated with 25(OH)D (p < 0.05; RXRA, NADSYN1/DHCR7, GC, or CYP27B1). We observed an interaction between 25(OH)D and methylation at cg21201924 in relation to breast cancer risk (ratio of hazard ratios = 1.22, 95% confidence interval 1.10-1.34; p = 7 × 10
CONCLUSIONS: 25(OH)D concentrations were associated with DNA methylation of CpGs in several vitamin D-related genes, with potential links to immune function-related genes. Methylation of CpGs in vitamin D-related genes may interact with 25(OH)D to affect the risk of breast cancer.

BACKGROUND: Genistein (5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is the most abundant isoflavone in soybean, which has been associated with a lower risk of development of cancer and cardiovascular diseases. Of particular interest regarding cancer preventive properties of flavonoids is their interaction with cytochrome P450 enzymes (CYPs). However, contradictory data report the effect of genistein on expression of СYPs enzymes.
OBJECTIVE: The aim of this study was to investigate the effects of genistein on cytochrome P450 (CYP) gene expression levels in human hepatocellular carcinoma (HepG2/C3A) and colon adenocarcinoma (HT29) cells.
METHODS: Real-time RT-PCR was used to examine the expression of genes families involved in xenobiotic metabolism, such as CYP1 (CYP1A1, CYP1B1), CYP2 (CYP2E1, CYP2D6), CYP3 (CYP3A4); and of a family involved in the catabolism of the all-trans-retinoic acid (ATRA), CYP26 (CYP26A1, CYP26B1).
RESULTS: RT-qPCR data analysis showed that after 12 h of exposure of HepG2/C3A cells to genistein (5 and 50 µM) there was an upregulation of CYP1A1 and CYP1B1 and downregulation of CYP2D6, CYP26A1 and CYP26B1 mRNA levels. There was no change in the mRNA levels of CYP P450 genes in HT29 cells.
CONCLUSION: Our results suggest that treatment with genistein in non-toxic concentrations may impact the expression level of CYPs involved in the biotransformation of xenobiotics and drug metabolizing enzymes. Moreover, the downregulation of ATRA metabolism-related genes opens a new research path for the study of genistein as retinoic acid metabolism blocking agent for treating cancer and other pathologies.

Colorectal cancer (CRC) is the neoplasia that is most frequently associated with vitamin D deficiency in epidemiological and observational studies in terms of incidence and mortality. Many mechanistic studies show that the active vitamin D metabolite (1α,25-dihydroxyvitamin D

Aim of Study: Results on the association of Vitamin D receptor (VDR) gene polymorphism with renal cell carcinoma (RCC) susceptibility from the present reports are still debating. This meta-analysis was conducted to assess the association of VDR ApaI (rs7975232), BsmI (rs1544410), TaqI (rs731236), and Fok1 (rs2228570) gene polymorphisms with RCC risk.
Materials and Methods: The association studies were recruited from PubMed on May 1, 2016, and eligible reports were extracted and data were synthesized using meta-analysis method.
Result: Six investigations were included into this meta-analysis for the relationship between VDR gene polymorphism and RCC susceptibility. In this meta-analysis, the ApaI A allele, AA genotype, aa genotype, and Fok1 FF genotype were associated with RCC susceptibility in Asians. However, VDR BsmI and TaqI gene polymorphisms were not associated with the RCC risk in Asians, Caucasians, and overall populations. Furthermore, Fok1 gene polymorphism was not associated with the RCC risk in Caucasians and overall populations.
Conclusion: ApaI gene polymorphism and Fok1 FF genotype were associated with RCC susceptibility in Asians.

All-trans-retinoic acid (ATRA) and 1α,25-dihydroxyvitamin D (1,25D) are potent inducers of differentiation of myeloid leukemia cells. During myeloid differentiation specific transcription factors are expressed at crucial developmental stages. However, precise mechanism controlling the diversification of myeloid progenitors is largely unknown, CCAAT/enhancer-binding protein (C/EBP) transcription factors have been characterized as key regulators of the development and function of the myeloid system. Past data point at functional redundancy among C/EBP family members during myeloid differentiation. In this study, we show that in acute myeloid leukemia (AML) cells, high expression of vitamin D receptor gene (