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. Author manuscript; available in PMC: 2014 Jul 1.
Published in final edited form as: J Steroid Biochem Mol Biol. 2013 Jan 16;136:86–93. doi: 10.1016/j.jsbmb.2013.01.001

The sum of many small changes: microRNAs are specifically and potentially globally altered by vitamin D3 metabolites

Angeline A Giangreco a, Larisa Nonn a,b,*
PMCID: PMC3686905  NIHMSID: NIHMS436837  PMID: 23333596

Abstract

Vitamin D3 deficiency is rampant which may contribute to increased risk of many diseases including cancer, cardiovascular disease and autoimmune disorders. Genomic activity of the active metabolite 1,25-dihydroxyvitamin D (1,25D) mediates most vitamin D3's actions and many gene targets of 1,25D have been characterized. As the importance of non-coding RNAs has emerged, the ability of vitamin D3 via 1,25D to regulate microRNAs (miRNAs) has been demonstrated in several cancer cell lines, patient tissue and sera. In vitamin D3 intervention patient trials, significant differences in miRNAs are observed between treatment groups and/or between baseline and followup. In patient sera from population studies, specific miRNA differences associate with serum levels of 25D. The findings thus far indicate that dietary vitamin D3 in patients and 1,25D in vitro not only regulate specific miRNA(s), but may also globally upregulate miRNA levels.

This article is part of a Special Issue entitled ‘Vitamin D Workshop’.

Keywords: Vitamin D3, microRNAs

1. Introduction

The dietary and UV-induced prohormone vitamin D3 has pleiotropic effects that include regulation of calcium homeostasis, anti-inflammatory and potentially cancer prevention and/or treatment properties [1]. Population studies have shown that a low vitamin D3 status is associated with increased risk of colon [2], breast [3,4], prostate [5,6] and other cancers [7]. Moreover, a recent cohort analysis showed that low vitamin D3 status increased risk of death from all cancers [8].

In addition to natural dietary and supplemental vitamin D3, sun exposure triggers formation of vitamin D3 (cholecalciferol) in the skin. Cholecalciferol is metabolized into 25-hydroxyvitamin D3 (25D), primarily by the liver. 25D, or “circulating vitamin D”, is typically measured as an indicator of “vitamin D status”. Circulating 25D is further metabolized by the kidney to the active metabolite, 1,25-dihydroxyvitamin D3 (1,25D) [1], which regulates gene transcription via binding of 1,25D to the vitamin D receptor (VDR). VDR interacts with vitamin D response elements (VDREs) in the DNA, positively or negatively regulating gene transcription [1]. ChIP-seq data for VDR in immune cells has identified thousands of VDREs in the genome [9,10], but ChIP-seq identification of VDR binding sites is yet to be determined in other tissue types. Interestingly, 1,25D-regulated genes highly differ between tissues and cell types, a phenomenon that Zhang et al. recently suggested may be due to ligand-induced and DNA binding-induced alterations in VDR structure and activity [11]. Non-genomic “rapid actions” of vitamin D3 have been reported and are dependent on membrane VDR [12].

Given the strong genomic actions of 1,25D, and the reality that only 1.5% of our genome contains protein-coding genes [13, 14], it is likely that 1,25D also regulates the expression of some of the remaining genome with includes non-coding RNAs (ncRNAs). Non-coding areas are among the ultra-conserved elements (>95% identity with chicken, dog, mouse, rat) in the genome [15]. microRNAs (miRNAs) are a class of small ncRNAs that function by binding to imperfect complementary sites in the 3′-untranslated region (UTR) of target mRNAs, decreasing mRNA stability and/or decreasing protein translation [16]. miRNA are predicted to regulate 30% of all coding genes [17]. Mature miRNAs (18–25 nucleotides) are the result of post-transcription processing of longer nuclear encoded-hairpin pri-miRNAs. Drosha is a ribonuclease that resides in the nucleus and processes the full length pri-miRNA transcript into a hairpin pre-miRNAa which is exported into the cytosol for further processing by Dicer into the mature single stranded miRNA [18]. Pri-miRNAs can be transcribed independently when they are situated in intergenic regions or located on the antisense strands of annotated genes [19]. Other pri-miRNAs are encoded in intronic regions of host genes [19]. The transcriptional control of pri-miRNA expression remains incomplete. In the cytosol, mature miRNAs incorporate into the RNA-induced silencing complex (RISC) to silence mRNAs [18]. The pleotropic effect of miRNAs lies in their promiscuity and ability for one miRNA to regulate the expression of multiple target mRNAs.

Aberrant miRNA levels are found in cancers [20] and some miRNAs have been shown to influence the initiation and progression of human cancer. The importance of miRNAs in cancer was first demonstrated in the deletion of miRs-15 and 16-1 and the subsequent observation of increased expression of Bcl-2 in B-cell chronic lymphocytic leukemia (CLL) [2123]. Since that seminal discovery, miRNA profiling in cancers has exploded. Tumor-associated changes in miRNAs have been shown to occur by gene deletion/amplification, epigenetic mechanisms and by alterations in the miRNA processing machinery [20]. Expression profiling of cancers has identified miRNA signatures in cancers that associate with diagnosis, staging, progression, prognosis and response to treatment [20]. A defined role for individual miRNA changes has not been characterized for many of the cancer-related miRNAs because their function(s) is still unknown.

Interestingly, human tumors show a marked widespread reduction in miRNA levels [24]. This reduction in miRNA levels may be an attribute of stem-like properties and contribute to epigenetic abnormalities in cancer as reduction of global miRNAs expression disrupts maintenance of DNA hypermethylation [25]. Specific roles for miRNAs have emerged in the stem cells of developing animals [26]. It follows that in cancer, where cells regain “stemness”, miRNAs would be also involved.

Irrespective of the role of miRNAs during carcinogenesis, miRNAs are potential powerful biomarkers as they are aberrantly expressed in cancer and resistant to degradation in serum and tissues [27,28]. Multiple freeze–thaw cycles and storage at ambient temperature have no effect on miRNA detection in plasma and serum [28]. As well, miRNAs remain stable in archival formalin-fixed paraffin-embedded (FFPE) tissues [29,30]. Because of their remarkable stability, miRNAs are ideal biomarkers that can be explored in both archival and prospective specimens.

Despite the well characterized genomic actions of 1,25D and the vital role of miRNAs in fundamental cell biology, there are very few studies that examine regulation of miRNAs by 1,25D directly or as a result of dietary vitamin D3. Here we review the current findings on miRNAs that are altered by dietary vitamin D3 or directly via its metabolites.

2. Regulation of miRNAs by 1,25D and vitamin D3

2.1. Prostate cancer

Vitamin D3 has anti-cancer and chemopreventive activities in the prostate. Laboratory and in vivo rodent studies strongly support an anti-cancer activity for vitamin D3 in the prostate, whereas epidemiologic evidence obtained from serum levels of vitamin D3 metabolites show mixed results (reviewed in [1,31]). Interestingly, low serum levels of 25D are consistently associated with increased risk of P PCa mortality [5,32], but not consistently associated with overall PCa risk [31], suggesting vitamin D3 may be important in protecting against aggressive forms of PCa. Another layer to local vitamin D3 action is that PCa cells have reduced vitamin D3 1α-hydroxylase activity, which may lead to a disconnect between serum 25D levels and prostatic 1,25D bioavailability [33]. 1,25D regulates the expression of hundreds of genes in normal prostate cells and PCa cells, as shown by cDNA microarray analysis [34,35].

MiRNA expression signatures specific to PCa have been reported [3642]. These PCa-related miRNA signatures provide a foundation for future research, but they need to be tested in a larger number of specimens and the biological role of the PCa-specific miR alterations have yet to be studied. In PCa, several studies have shown global repression of miRs [24] or an imbalance of more down-regulated miR than upregulated miRs [24,38,40,43]. Dicer levels are increased in PCa and associate with an aggressive cancer phenotype, which does not implicate dicer as the mechanism for widespread miRNA reduction in PCa [44].

Three studies have examined the effect of 1,25D on miRNA expression in prostate cells and one study examined patient prostate tissue. Wang et al. [45] found that fifteen miRNAs were differentially regulated by 2.0-fold by combination treatment with 1,25D (100 nM) and testosterone (5 nM) (T + D) in LNCaP cells. Overall, around 80% of the regulated miRNAs were upregulated by T + D particularly; miR-134, miR-22, and miR-29a/b while only miR-17 and miR-20a/b were downregulated (Table 1). Wang et al. suggest that the synergistic effect of 1,25D and testosterone have more significant effects on miRNA expression than either on their own. In another study, miR-106b alone was shown to be upregulated by 1,25D in prostate cells and contribute to p21 mediated cell-cycle arrest [46].

Table 1.

MiRNAs regulated by 1,25D or 25D in vitro.

Cells Organ Dose vitamin D miRNAs References
Total profiled/method Up-regulated Down-regulated
in vitro LNCaP cells Prostate 100 nM 1,25(OH)2D3(48 H) 866 miRNA microarray miR-542-5p miR-371-5p miR-17 Wang et al. [45]
miR-29b miR-663 miR-20a
miR-1207-5p miR-134 miR-20b
miR-22 miR-135a*
miR-1915 miR-1181
miR-29a miR-629*
Melanoma cells Skin 10−8 M 1,25(OH)2D3(24 H) 2 qRT-PCR n/a miR-125b Essa et al. [70]
miR-27b
MCF12F cells Breast [250nmol/L 25(OH)2D3 + stress] 1350 miRNA microarray miR-98 miR-26b let-7e Peng et al. [55]
miR-21 miR-182 let-7b
miR-422b miR-203 miR-205
miR-30c let-7a miR-200b
miR-93 miR-191 miR-92
miR-20b let-7f let-7d
miR-106a miR-200c
miR-18a miR-16
Colon cancer cells (SW480-ADH) Colon 10−7 M 1,25(OH)2D3 (2 48, 96 H) 1350 miRNA Microarray miR-22 miR-93 Alvarez-Diaz
miR-21 miR-20b et al. [60]
miR-224 miR-106a
miR-222 miR-18a
miR-146a/b
Human myeloid leukemia cells (HL60-G and U937) Blood 10nmol/L 1,25(OH)2D3 (U937) 1 nmol/L 1,25(OH)2D3 (HL60) 245 miRNA microarray (Garzon 2007) miR-32 n/a Gocek et al. [80]
Human myeloid leukemia cells (HL60-G and U937) Blood Blood 10nmol/L 1,25(OH)2D3(U9371 nmol/L 1,25(OH) D (HL60) 245 245 miRNA microarray (Garzon 2007) n/a miR-181a Wang et al. [81]
miR-181b
RWPE-1 cells Prostate 1,25(OH)2D3 (100nM) 1 qRT-PCR miR-106b n/a Thorne et al. [46]
Primary Prostate 50nM 1,25(OH)2D3 667 qRT-PCR array 1 H: miR-320 1 H: Giangreco et al. [93]
prostate cells (1 H or 24 H) miR-92 miR-132 miR-103
miR-27b miR-135b miR-339-3p
24 H: miR-103 miR-130a
miR-24 miR-365 24 H:
miR-140-5p miR-99b miR-196b
miR-339-3p miR-125a-5p
miR-301a miR-141
miR-342-3p miR-138
miR-345 miR-26a
miR-374b miR-29a
miR-30c miR-28-3p
miR-106b miR-429
miR-708 miR-31
miR-100** miR-29c
miR-331-3p miR-452
miR-125b** miR-744
miR-126

Our group has analyzed the regulation of miRNAs by 1,25D (50 nM) and vitamin D3 (cholecalciferol) in prostate cells and in patient tissue respectively [93]. In vitro, miR-100 and miR-125b, were upregulated while their targets PLK1 and E2F3 were down-regulated by 1,25D in a VDR-dependant manner [93] (Table 1). Validation of the cell culture findings in PCa patients given oral vitamin D3 for 3–8 weeks prior to radical prostatectomy demonstrated local prostatic 1,25D concentrations positively correlated with the miRs (miR-100, miR-125b, miR-106b, miR-141, miR-331-3p, miR-103, let-7a, and let-7b) in normal and/or PCa epithelium (Table 2). As well, there was an overall downregulation of miRNAs in PCa regions compared to benign [93]. These results show that vitamin D3 may globally augment miRNAs in both benign and PCa tissue in patients.

Table 2.

MiRNAs associated with serum or tissue levels of vitamin D3 metabolites in patients.

Cells/tissue Organ Dose vitamin D miRNAs References
Total profiled/method Up-regulated Down-regulated
Patient specimens Plasma (males) Plasma Vitamin D3 supplementation in males: Pilot study 1: 40,000 IU/week for 1 year (N=5) Pilot study 2: for 1 year (N=5) Main study: for 12 months [20,000 (N=19) or 40,000 (N= 21) IU/week or placebo (N=37)]-males 730 Pilot 1 qRT-PCR let-7f miR-543 miR-106b Jorde et al. [77]
742 Pilot 2 miR-133b miR-766 miR-19a
12 Main miR-26a miR-15b miR-22
miR-28-5p miR-191 miR-424
miR-338-3p miR-221 miR-548b-3p
let-7a miR-331-3p miR-660
let-7d miR-339-5p miR-324-5p
miR-146a miR-374b mR-532-3p
miR-151-3p/5p miR-99b
Plasma (pregnant women) Plasma Participants (N= 13) with low (<25.5 ng./ml) and high (>31.7 ng/ml) 25(OH)2D3 1884 OneArray™ miR-589 miR-320d miR-574-5p Enquobahrie
miRNA miR-601 miR-423-3p et al. [85]
microarray miR-573 miR-484
miR-196a* miR-93
miR-92b
miR-138
(Comparing high to low 25D concentrations)
LCM-collected human prostate epithelium Prostate Vitamin D3 [400, 10,000, 40,000 IU/day for 3-8 weeks] 12 qRT-PCR Benign: PCa: n/a Giangreco et al. [93]
miR-141 miR-100
miR-103 miR-125b
miR-100 miR-106b
miR-125b miR-141
let-7a miR-103
let-7b miR-331-3p
let-7a
let-7b
(miRNA with positive correlation to 1,25 and/or25D)

2.2. Breast cancer

Low serum 25D levels are associated with decreased breast cancer risk [47]. Goodwin et al. [48] found that in a study of 535 women 75 years in age or younger, vitamin D3 deficiency was associated with distant recurrence and mortality. They also found similar results to Neuhouser and colleagues who found that 75% of breast cancer survivors were deficient in vitamin D3 by serum 25D levels [49]. In contrast, a nested-case control study of 512 breast cancer patients and matched controls, found no significant association between recurrence, survival, and serum 25D after breast cancer treatment [50]. While epidemiological studies show varied results, in vivo 1,25D analog EB1089 reduced growth of breast cancer tumors in mice [51] by inducing apoptosis [51]. In mice, supplementation with vitamin D3 and calcium prevented western style diet (high fat diet)-induced mammary hyperproliferation [52].

MiRNA expression can differentiate breast cancer from benign tissue with high accuracy, as well, particular features associated with breast cancer such as estrogen or progesterone receptor expression, lymph node metastasis, vascular invasion, proliferation, and p53 can be identified from miRNA profiles [21]. Iorio et al. identified miR-10b, miR-125b, and miR-145 as miRNAs that were consistently expressed at a lower level in tumor areas while miR-21 and miR-155 were upregulated. The expression of miR-206, miR-335, and miR-126, tumor suppressive miRNAs, is absent in metastatic tumor cells and these miRNAs suppress breast cancer metastasis to lung and bone [53]. Dicer expression may also be a predictor of breast tumor and metastasis as dicer levels were decreased in patients with recurrence and in breast cancer cell lines and low levels were associated with metastasis [54].

In MCF12F breast cancer cells, 25D regulated stress-induced miRNAs [55]. Microarray profiling in stressed cells (induced by serum starvation) upregulated miR-26b, miR-182, and let-7a and downregulated miR-18a, miR-106, and miR-30c by 2.0-fold. Pretreatment with 25D (250 nmol/L) inhibited/reversed the stress-induced miRNA changes in expression (Table 1). MiRNA expression in 25D-treated cells without stress was not included in this study. Stressors in the form of hypoxia, oxidative stress, serum starvation, inflammatory stress, and heat-shock-induced stress are potential induces of cancer and can alter cancer progression. The ability of 25D to target stress-induced miRNAs suggests a mechanism involved in its chemopreventive role in breast cancer [55].

2.3. Colon cancer

In 1989 a US study first reported that serum 25D was inversely correlated with colorectal cancer [2]. A meta-analysis of that pivotal 1989 study and eight additional clinical studies further validated the inverse association between serum 25D levels and colorectal cancer risk [47]. In clinical patient specimens VDR levels are increased early in colon cancer but are greatly reduced in the later stages [56]. In vivo, Balb/c mice given a vitamin D3-deficient diet had larger tumors, and decreased VDR and CYP27B1 expression than vitamin D-sufficient mice [57]. Mice given a western style diet (with low calcium and vitamin D3 and high fat) develop colonic tumors while supplementation with calcium and vitamin D3 reduced tumor progression, suggesting that vitamin D3 deficiency is involved in tumor progression [58].

Similarly to other cancers, miRNAs are dysregulated in colon cancer. In colon cancer miRNAs have been shown to be diagnostic (miR-17-3p and miR-92a) and prognostic markers (miR-21) and suitable predictors of treatment outcome (let-7 and miR-181b) (as reviewed by [59]).

Alvarez-Diaz et al. demonstrated that tumor suppressive, miR-22 is induced by 1,25D in a VDR-dependent manner and exerts anti-proliferative and anti-migratory effects when overexpressed in human colon cancer cells [60] (Table 1). A 48 h treatment with 1,25D (100nM) augmented miR-22 expression and regulated vitamin D target genes OGN, NELL2, HNRH1, RERE and NFAT5. In matched normal and tumor samples from colon cancer patients, miR-22 levels were lower in 78% of tumor and miR-22 expression positively correlated with the VDR expression, which was also lower (72%) in tumor samples. Independent of vitamin D3, others found that miR-22 regulates angiogenesis, via suppression of hypoxia inducible factor 1 and VEGF, in colon cancer cells and confirmed that miR-122 levels are lower in colon cancer versus benign colonic epithelium [61]. Therefore, miR-22 may be a significant part of the chemopreventive activity of vitamin D3 in colon cancer.

2.4. Melanoma

Vitamin D3 is synthesized in the skin from sun exposure and that UV exposure is also the major risk factor for skin cancers [62], making the role of vitamin D3 in melanoma somewhat complicated. In vitro, Colston et al. first demonstrated that melanoma cells express the VDR and that 1,25D is anti-proliferative [63]. A cohort study also demonstrated that high 25D levels at diagnosis were protective of melanoma relapse and mortality suggesting that vitamin D3 supplementation may protect melanoma patients from relapse [64]. Another study found that a VDR promoter polymorphism, A-1012G, increased occurrence and metastasis development of malignant melanoma [65].Various studies have profiled miRNAs in melanoma tissue and cells [6668]. One study identified miRNAs (4 upregulated/11 downregulated in 8 melanoma cells lines) that could distinguish melanoma from other solid tumors [66]. Due to inconsistent published findings on melanoma and miRNAs, Philippidou and colleagues profiled 9 melanoma cell lines and 20 patient samples (3 benign/20 melanoma metastasis) where they identified miR-200c, as did Gaur et al. [66], as downregulated both in vitro and in patients [68]. Dicer expression is also altered in melanoma where protein levels where increased in melanoma tissue [69].

Essa et al. examined the effect of 1,25D (10nM) on melanoma cells and identified miR-125b as downregulated when VDR was increased [70]. However, knockdown of miR-125b did not alter VDR mRNA and protein levels [70]. Basal levels of miR-125b were also lower in 1,25D-responsive melanoma cell lines (MeWo and SK-Mel28) compared to primary melanocytes [70]. miR-125b may be involved in the early progression of melanoma as it was downregulated in early metastasis of cutaneous melanoma [71] and knockdown of miR-125b enhanced the metastatic capability though the inhibition of senescence and apoptosis [72].

2.5. Leukemia

Differentiation therapy is a useful treatment in hematological malignancies. The earliest report of 1,25D's involvement in differentiation of leukemia cells was in the human promyelocytic leukemia cell line, HL60 [73] Then Munker et al. demonstrated that 1,25D was also anti-proliferative in leukemia cells [74]. Numerous other studies have further shown the anti-proliferative and pro-differentiating property of vitamin D3 in vivo and in vitro. Analysis of UVB exposure and leukemia incidence around the world, demonstrated that serum vitamin D3 status may be predictive of leukemia risk [75,76]. Human studies with vitamin D3 (or analogs) alone or in combination therapy have seen minimal effects on survival and/or rates/duration or remission as reviewed by [77]. Further studies to understand the mechanism of vitamin D3 on the immune system as well as clinical trials with more effective vitamin D3 analogs may be beneficial in the treatment of leukemia's with vitamin D3.

The seminal study that demonstrated miRNA involvement cancer was in chronic lymphocytic leukemia (CLL) patients where miR-15a and miR-16-1 were downregulated due to a genomic deletion [78]. Further studies identified differential miRNA patterns between normal and leukemia patient tissue, aberrant miRNA expression in malignancy, and miRNAs involved in hematoposisis (as reviewed by [79]).

In acute myeloid leukemia cells, both miR-181a/b and miR-32 are regulated by 1,25D [80,81]. HL60 and U937 cells treated with 1,25D (0.1–100nM) for 48h downregulated both miR-181a and more so miR-181b. Wang et al. demonstrated that 1,25D augmented cell cycle regulator p27Kip1 and transfection with a pre-miR-181a abrogated that effect suggesting that 1,25D and miR-181 are involved in the control of cell cycle transition in myeloid leukemia [81]. 1,25D also can alter pro-survival mechanisms in HL60 and U937 cells through its regulation of miR-32 [80]. Gocek et al. found that 1,25D-induced miR-32, regulated pro-apoptotic Bim. Further, decreased miR-32 expression made AML cells more susceptible to agents like AraC that are used to treat this disease [80].

2.6. Serum

miRNAs are differentially expressed in both serum and plasma of cancer patients, and may serve as potential biomarkers for cancer diagnosis and prognosis [82,83]. In pregnant women, Enquobahrie et al. demonstrated that vitamin D3-deficiency was associated with differential miRNAs levels (10 downregulated and 1 upregulated) (Table 2) compared to women with normal serum 25D. Pregnant women often have vitamin D3 insufficiency or deficiency [84] which may lead to increased risk of pregnancy-related complications such as gestational diabetes, preeclampsia, and bacterial vaginosis [85,86].

Jorde and colleagues examined a 730 miRNAs in two pilot studies of patients given 4000IU/day of vitamin D3 for 12 months and identified 18 miRNAs that were unregulated by vitamin D3 and 8 that were downregulated [77] (Table 2). 12 miRNAs were examined in their main study and only miR-532-3p had weak correlation to serum 25D [77].

3. Mechanism

While studies show that vitamin D3 or its metabolites alter the levels of some miRNAs, the mechanism of regulation is not necessarily straight forward. Canonical VDR-mediated regulation of miRNAs via VDREs (vitamin D response element) has been demonstrated for several miRNAs and may mediate regulation of other miRNAs. Briefly, Peng et al. analyzed the 1 kb 5′ flanking sequence of the miR-132 and let-7a pri-miRNAs and found multiple VDR/RXR binding sites in some of the miRs regulated by stress/25D [55]. Adding complexity to the mechanism, there also appears to be a negative feedback loop between miRNAs and VDR. Mohri et al. demonstrated that overexpression of miR-125b reduced VDR/RXRα protein levels post-transcriptionally in MCF-7 cells [92], although direct regulation of miRNAs by 1,25D was not assessed in this study.

Taking a birds' eye look at the studies so far, it appears that in addition to direct VDRE-mediated regulation of specific miRNAs, vitamin D3 may globally augment miRNA expression. All of the in vitro and patient studies that did full miRNA profiling identified more miRNAs upregulated by vitamin D3 (or 1,25D) than downregulated miRNAs [59,60,77,85], with the exception of one study which did not analyze miRNAs regulated by 1,25D in the absence of stress [55]. Several mechanisms may cause such a global effect. One explanation is that vitamin D3 alters the miRNA processing machinery, but this has not been reported. Another mechanism for global regulation of miRNAs by vitamin D3 is a VDR-dependent chromatin opening which increases pri-miRNA transcription globally. In support of this mechanism, Disanto et al. found that VDR binding alters chromatin states that determine areas of the genome that are accessible to transcription factor binding and to the activation or inhibition of transcription [87]. Given the heterogeneity in VDRE consensus sequences and the discovery of very distal VDREs up to 100kb away from the transcription start site [9,10], it maybe technically challenging to assess non-VDRE-dependent mechanisms of 1,25D-regulated miRNAs.

Non-genomic VDR-dependent activity of 1,25D may also alter miRNA levels by effecting miRNA stability or processing pathway, although in the literature there is not yet evidence that this has been examined. Consistent with this hypothesis, KHSRP and TARDBP, proteins involved in miRNA processing and regulation of miRNA biogenesis and maturation [88,89], were upregulated by 1,25D in colon cancer cells [69].

4. Significance and conclusions

Many of the vitamin D-regulated miRNAs (let-7a, let-7b, miR-100, miR-125b, miR-100, miR-106b, miR-141, miR-103, miR-331-3p) alter cell phenotypes in a manner consistent with tumor suppressor activity and other activities of vitamin D3. However, miRNAs identified thus far have been cell type specific with little overlap, consistent with tissue-specific VDR activity. Notably, the potential for vitamin D3 to induce widespread miRNA upregulation is of high significance to cancer in which there is a global suppression of miRNAs [24,37,42,90,91]. Further examination of vitamin D3 effects on global miRNA levels by RNAseq in animal models and in clinical trial specimens are needed to validate and describe this potentially powerful action of vitamin D3. Vitamin D3 may also be important in maintaining normal miRNA expression as Peng and colleagues, demonstrated that 1,25D reversed the stress-induced changes in miRNA expression in breast cancer cells back to baseline [55].

Although regulation of any one miRNA by vitamin D3 may not seem significant in cell function, these small changes may add up to the preservation of overall health in persons with vitamin D3 sufficiency. It makes sense that vitamin D3, an essential hormone, modulates many aspects of normal cell function. It is the recent prevalence of vitamin D3 deficiency, and diseases linked to that deficiency, that has brought the identification of mechanisms of vitamin D3 action to forefront of research. In general health practice vitamin D3 is not an intervention or drug, but rather part of overall health and that maintenance of vitamin D3 sufficiency is as important as other markers of health (i.e. low serum cholesterol). In regards to non-coding RNAs, basic research in this area is still in its infancy and what we do not know far outweighs what we do know. The reality that many of the ultraconserved elements of the genome are non-coding regions, signifies that these regions are vital to mediating our genetic code. It is then not surprising that maintaining vitamin D3 sufficiency is also important in safeguarding the expression of our non-coding genome. While miRNAs are the focus of this review and the majority of ncRNA research, regulation of long-ncRNAs, snoRNAs and pseudogenes (among other ncRNAs) by 1,25D may also contribute to the role of vitamin D3 in maintaining cell health.

References

  • 1.Krishnan AV, Peehl DM, Feldman D. In: Vitamin D and Prostate Cancer. Vitamin D, Glorieux FH, editors. Elsevier Academic Press; San Diego: 2005. pp. 1679–1707. [Google Scholar]
  • 2.Garland CF, et al. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet. 1989;2(8673):1176–1178. doi: 10.1016/s0140-6736(89)91789-3. [DOI] [PubMed] [Google Scholar]
  • 3.Engel P, et al. Serum 25(OH) vitamin D and risk of breast cancer: a nested case-control study from the French E3N cohort, Cancer Epidemiology. Biomarkers and Prevention. 2010;19(9):2341–2350. doi: 10.1158/1055-9965.EPI-10-0264. [DOI] [PubMed] [Google Scholar]
  • 4.Engel P, et al. Joint effects of dietary vitamin D and sun exposure on breast cancer risk: results from the French E3N cohort, Cancer Epidemiology. Biomarkers and Prevention. 2011;20(1):187–198. doi: 10.1158/1055-9965.EPI-10-1039. [DOI] [PubMed] [Google Scholar]
  • 5.Shui IM, et al. Vitamin d-related genetic variation, plasma vitamin d, and risk of lethal prostate cancer: a prospective nested case–control study. Journal of the National Cancer Institute. 2012;104(9):690–699. doi: 10.1093/jnci/djs189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Tretli S, et al. Association between serum 25(OH)D and death from prostate cancer. British Journal of Cancer. 2009;100(3):450–454. doi: 10.1038/sj.bjc.6604865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Giovannucci E, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. Journal of the National Cancer Institute. 2006;98(7):451–459. doi: 10.1093/jnci/djj101. [DOI] [PubMed] [Google Scholar]
  • 8.Pilz S, et al. Low serum levels of 25-hydroxyvitamin D predict fatal cancer in patients referred to coronary angiography, Cancer Epidemiology. Biomarkers and Prevention. 2008;17(5):1228–1233. doi: 10.1158/1055-9965.EPI-08-0002. [DOI] [PubMed] [Google Scholar]
  • 9.Heikkinen S, et al. Nuclear hormone 1α,25-dihydroxyvitamin D3 elicits a genome-wide shift in the locations of VDR chromatin occupancy. Nucleic Acids Research. 2011;39(21):9181–9193. doi: 10.1093/nar/gkr654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Ramagopalan SV, et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Research. 2010;20(10):1352–1360. doi: 10.1101/gr.107920.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Zhang J, et al. DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex. Nature Structural and Molecular Biology. 2011;18(5):556–563. doi: 10.1038/nsmb.2046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Norman AW, Mizwicki MT, Norman DP. Steroid-hormone rapid actions: membrane receptors and a conformational ensemble model. Nature Reviews Drug Discovery. 2004;3(1):27–41. doi: 10.1038/nrd1283. [DOI] [PubMed] [Google Scholar]
  • 13.Lander ES, Chen YJ. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860–921. doi: 10.1038/35057062. [DOI] [PubMed] [Google Scholar]
  • 14.Venter JC, Zhu X. The sequence of the human genome. Science. 2001;291(5507):1304–1351. doi: 10.1126/science.1058040. [DOI] [PubMed] [Google Scholar]
  • 15.Bejerano G, et al. Ultraconserved elements in the human genome. Science. 2004;304(5675):1321–1325. doi: 10.1126/science.1098119. [DOI] [PubMed] [Google Scholar]
  • 16.Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–297. doi: 10.1016/s0092-8674(04)00045-5. [DOI] [PubMed] [Google Scholar]
  • 17.Garzon R, et al. MicroRNA expression and function in cancer. Trends in Molecular Medicine. 2006;12(12):580–587. doi: 10.1016/j.molmed.2006.10.006. [DOI] [PubMed] [Google Scholar]
  • 18.Tsuchiya S, Okuno Y, Tsujimoto G. MicroRNA: biogenetic and functional mechanisms and involvements in cell differentiation and cancer. Journal of Pharmaceutical Sciences. 2006;101(4):267–270. doi: 10.1254/jphs.cpj06013x. [DOI] [PubMed] [Google Scholar]
  • 19.Zhou Y, et al. Inter- and intra-combinatorial regulation by transcription factors and microRNAs. BMC Genomics. 2007;8:396. doi: 10.1186/1471-2164-8-396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Calin GA, Croce CM. MicroRNA signatures in human cancers. Nature Reviews Cancer. 2006;6(11):857–866. doi: 10.1038/nrc1997. [DOI] [PubMed] [Google Scholar]
  • 21.Calin GA, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. New England Journal of Medicine. 2005;353(17):1793–1801. doi: 10.1056/NEJMoa050995. [DOI] [PubMed] [Google Scholar]
  • 22.Calin GA, et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(32):11755–11760. doi: 10.1073/pnas.0404432101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Cimmino A, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(39):13944–13949. doi: 10.1073/pnas.0506654102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Lu J, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834–838. doi: 10.1038/nature03702. [DOI] [PubMed] [Google Scholar]
  • 25.Ting AH, et al. A requirement for DICER to maintain full promoter CpG island hypermethylation in human cancer cells. Cancer Research. 2008;68(8):2570–2575. doi: 10.1158/0008-5472.CAN-07-6405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Stadler BM, Ruohola-Baker H. Small RNAs: keeping stem cells in line. Cell. 2008;132(4):563–566. doi: 10.1016/j.cell.2008.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Chen X, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Research. 2008;18(10):997–1006. doi: 10.1038/cr.2008.282. [DOI] [PubMed] [Google Scholar]
  • 28.Mitchell PS, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(30):10513–10518. doi: 10.1073/pnas.0804549105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Doleshal M, et al. Evaluation and validation of total RNA extraction methods for microRNA expression analyses in formalin-fixed: paraffin-embedded tissues. Journal of Molecular Diagnostics. 2008;10(3):203–211. doi: 10.2353/jmoldx.2008.070153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Nonn L, et al. mRNA and micro-RNA expression analysis in laser-capture microdissected prostate biopsies: valuable tool for risk assessment and prevention trials. Experimental and Molecular Pathology. 2010;88(1):45–51. doi: 10.1016/j.yexmp.2009.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States) Cancer Causes and Control. 2005;16(2):83–95. doi: 10.1007/s10552-004-1661-4. [DOI] [PubMed] [Google Scholar]
  • 32.Fang F, et al. Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS One. 2011;6(4):e18625. doi: 10.1371/journal.pone.0018625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Hsu JY, et al. Reduced 1α-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Research. 2001;61(7):2852–2856. [PubMed] [Google Scholar]
  • 34.Krishnan AV, et al. Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays. Prostate. 2004;59(3):243–251. doi: 10.1002/pros.20006. [DOI] [PubMed] [Google Scholar]
  • 35.Peehl DM, et al. Molecular activity of 1,25-dihydroxyvitamin D(3) in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. Journal of Steroid Biochemistry and Molecular Biology. 2004;92(3):131–141. doi: 10.1016/j.jsbmb.2004.07.003. [DOI] [PubMed] [Google Scholar]
  • 36.Mattie MD, et al. Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer. 2006;5:24. doi: 10.1186/1476-4598-5-24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ozen M, et al. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008;27(12):1788–1793. doi: 10.1038/sj.onc.1210809. [DOI] [PubMed] [Google Scholar]
  • 38.Porkka KP, et al. MicroRNA expression profiling in prostate cancer. Cancer Research. 2007;67(13):6130–6135. doi: 10.1158/0008-5472.CAN-07-0533. [DOI] [PubMed] [Google Scholar]
  • 39.Prueitt RL, et al. Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate. 2008;68(11):1152–1164. doi: 10.1002/pros.20786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Schaefer A, et al. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. International Journal of Cancer. 2010;126(5):1166–1176. doi: 10.1002/ijc.24827. [DOI] [PubMed] [Google Scholar]
  • 41.Tong AW, et al. MicroRNA profile analysis of human prostate cancers. Cancer Gene Therapy. 2009;16(3):206–216. doi: 10.1038/cgt.2008.77. [DOI] [PubMed] [Google Scholar]
  • 42.Volinia S, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(7):2257–2261. doi: 10.1073/pnas.0510565103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Ozen M, et al. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2007;27(12):1788–1793. doi: 10.1038/sj.onc.1210809. [DOI] [PubMed] [Google Scholar]
  • 44.Chiosea S, et al. Up-regulation of dicer: a component of the MicroRNA machinery, in prostate adenocarcinoma. American Journal of Pathology. 2006;169(5):1812–1820. doi: 10.2353/ajpath.2006.060480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Wang WL, et al. Effects of 1α,25-dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011;10:58. doi: 10.1186/1476-4598-10-58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Thorne JL, et al. Epigenetic control of a VDR-governed feed-forward loop that regulates p21(waf1/cip1) expression and function in non-malignant prostate cells. Nucleic Acids Research. 2011;39(6):2045–2056. doi: 10.1093/nar/gkq875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Gandini S, et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal: breast and prostate cancer and colorectal adenoma. International Journal of Cancer. 2011;128(6):1414–1424. doi: 10.1002/ijc.25439. [DOI] [PubMed] [Google Scholar]
  • 48.Goodwin PJ, et al. Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. Journal of Clinical Oncology. 2009;27(23):3757–3763. doi: 10.1200/JCO.2008.20.0725. [DOI] [PubMed] [Google Scholar]
  • 49.Neuhouser ML, et al. Vitamin D insufficiency in a multiethnic cohort of breast cancer survivors. American Journal of Clinical Nutrition. 2008;88(1):133–139. doi: 10.1093/ajcn/88.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Jacobs ET, et al. Vitamin D and breast cancer recurrence in the Women's Healthy Eating and Living (WHEL) Study. American Journal of Clinical Nutrition. 2011;93(1):108–117. doi: 10.3945/ajcn.2010.30009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.James SY, et al. EB1089: a synthetic analogue of vitamin D, induces apoptosis in breast cancer cells in vivo and in vitro. British Journal of Pharmacology. 1998;125(5):953–962. doi: 10.1038/sj.bjp.0702103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Xue L, et al. Influence of dietary calcium and vitamin D on diet-induced epithelial cell hyperproliferation in mice. Journal of the National Cancer Institute. 1999;91(2):176–181. doi: 10.1093/jnci/91.2.176. [DOI] [PubMed] [Google Scholar]
  • 53.Tavazoie SF, et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008;451(7175):147–152. doi: 10.1038/nature06487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Grelier G, et al. Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype. British Journal of Cancer. 2009;101(4):673–683. doi: 10.1038/sj.bjc.6605193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Peng X, et al. Protection against cellular stress by 25-hydroxyvitamin D3 in breast epithelial cells. Journal of Cellular Biochemistry. 2010;110(6):1324–1333. doi: 10.1002/jcb.22646. [DOI] [PubMed] [Google Scholar]
  • 56.Cross HS, et al. Vitamin D receptor and cytokeratin expression may be progression indicators in human colon cancer. Anticancer Research. 1996;16(4B):2333–2337. [PubMed] [Google Scholar]
  • 57.Tangpricha V, et al. Vitamin D deficiency enhances the growth of MC-26 colon cancer xenografts in Balb/c mice. Journal of Nutrition. 2005;135(10):2350–2354. doi: 10.1093/jn/135.10.2350. [DOI] [PubMed] [Google Scholar]
  • 58.Newmark HL, et al. Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer. Carcinogenesis. 2009;30(1):88–92. doi: 10.1093/carcin/bgn229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Wu WK, et al. MicroRNA in colorectal cancer: from benchtop to bedside. Carcinogenesis. 2011;32(3):247–253. doi: 10.1093/carcin/bgq243. [DOI] [PubMed] [Google Scholar]
  • 60.Alvarez-Diaz S, et al. MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative: antimigratory and gene regulatory effects in colon cancer cells. Human Molecular Genetics. 2012;21(10):2157–2165. doi: 10.1093/hmg/dds031. [DOI] [PubMed] [Google Scholar]
  • 61.Yamakuchi M, et al. MicroRNA-22 regulates hypoxia signaling in colon cancer cells. PLoS One. 2011;6(5):e20291. doi: 10.1371/journal.pone.0020291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Gandini S, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. European Journal of Cancer. 2005;41(1):45–60. doi: 10.1016/j.ejca.2004.10.016. [DOI] [PubMed] [Google Scholar]
  • 63.Colston K, Colston MJ, Feldman D. 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology. 1981;108(3):1083–1086. doi: 10.1210/endo-108-3-1083. [DOI] [PubMed] [Google Scholar]
  • 64.Newton-Bishop JA, et al. Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. Journal of Clinical Oncology. 2009;27(32):5439–5444. doi: 10.1200/JCO.2009.22.1135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Halsall JA, et al. A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibilty and prognosis in malignant melanoma. British Journal of Cancer. 2004;91(4):765–770. doi: 10.1038/sj.bjc.6602006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Gaur A, et al. Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Research. 2007;67(6):2456–2468. doi: 10.1158/0008-5472.CAN-06-2698. [DOI] [PubMed] [Google Scholar]
  • 67.Mueller DW, Rehli M, Bosserhoff AK. miRNA expression profiling in melanocytes and melanoma cell lines reveals miRNAs associated with formation and progression of malignant melanoma. Journal of Investigative Dermatology. 2009;129(7):1740–1751. doi: 10.1038/jid.2008.452. [DOI] [PubMed] [Google Scholar]
  • 68.Philippidou D, et al. Signatures of microRNAs and selected microRNA target genes in human melanoma. Cancer Research. 2010;70(10):4163–4173. doi: 10.1158/0008-5472.CAN-09-4512. [DOI] [PubMed] [Google Scholar]
  • 69.Cristobo I, et al. Proteomic analysis of 1α,25-dihydroxyvitamin D3 action on human colon cancer cells reveals a link to splicing regulation. Journal of Proteomics. 2011;75(2):384–397. doi: 10.1016/j.jprot.2011.08.003. [DOI] [PubMed] [Google Scholar]
  • 70.Essa S, et al. Signature of VDR miRNAs and epigenetic modulation of vitamin D signaling in melanoma cell lines. Anticancer Research. 2012;32(1):383–389. [PubMed] [Google Scholar]
  • 71.Glud M, et al. Downregulation of miR-125b in metastatic cutaneous malignant melanoma. Melanoma Research. 2010;20(6):479–484. doi: 10.1097/CMR.0b013e32833e32a1. [DOI] [PubMed] [Google Scholar]
  • 72.Glud M, et al. MicroRNA miR-125b induces senescence in human melanoma cells. Melanoma Research. 2011;21(3):253–256. doi: 10.1097/CMR.0b013e328345333b. [DOI] [PubMed] [Google Scholar]
  • 73.Miyaura C, et al. 1 α,25-DihydroxyvitaminD3 induces differentiation of human myeloid leukemia cells. Biochemical and Biophysical Research Communications. 1981;102(3):937–943. doi: 10.1016/0006-291x(81)91628-4. [DOI] [PubMed] [Google Scholar]
  • 74.Munker R, Norman A, Koeffler HP. Vitamin D compounds. Effect on clonal proliferation and differentiation of human myeloid cells. Journal of Clinical Investigation. 1986;78(2):424–430. doi: 10.1172/JCI112593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Mohr SB, et al. Ultraviolet B and incidence rates of leukemia worldwide. American Journal of Preventive Medicine. 2012;41(1):68–74. doi: 10.1016/j.amepre.2011.04.003. [DOI] [PubMed] [Google Scholar]
  • 76.Molica S, et al. Vitamin D insufficiency predicts time to first treatment (TFT) in early chronic lymphocytic leukemia (CLL) Leukemia Research. 2012;36(4):443–447. doi: 10.1016/j.leukres.2011.10.004. [DOI] [PubMed] [Google Scholar]
  • 77.Jorde R, et al. Plasma profile of microRNA after supplementation with high doses of vitamin D3 for 12 months. BMC Research Notes. 2012;5(1):245. doi: 10.1186/1756-0500-5-245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Calin GA, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(24):15524–15529. doi: 10.1073/pnas.242606799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Schotte D, Pieters R, Den Boer ML. MicroRNAs in acute leukemia: from biological players to clinical contributors. Leukemia. 2011;26(1):1–12. doi: 10.1038/leu.2011.151. [DOI] [PubMed] [Google Scholar]
  • 80.Gocek E, et al. MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Research. 2011;71(19):6230–6239. doi: 10.1158/0008-5472.CAN-11-1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Wang X, et al. MicroRNAs181 regulate the expression of p27Kip1 in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3. Cell Cycle. 2009;8(5):736–741. doi: 10.4161/cc.8.5.7870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Jackson DB. Serum-based microRNAs: are we blinded by potential? Proceedings of the National Academy of Sciences of the United States of America. 2009;106(1):E5. doi: 10.1073/pnas.0809999106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Lodes MJ, et al. Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS One. 2009;4(7):e6229. doi: 10.1371/journal.pone.0006229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Ginde AA, et al. Vitamin D insufficiency in pregnant and nonpregnant women of childbearing age in the United States. American Journal of Obstetrics and Gynecology. 2010;202(5):436e1–4368e. doi: 10.1016/j.ajog.2009.11.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Enquobahrie DA, et al. Global maternal early pregnancy peripheral blood mRNA and miRNA expression profiles according to plasma 25-hydroxyvitamin D concentrations. Journal of Maternal-Fetal and Neonatal Medicine. 2011;24(8):1002–1012. doi: 10.3109/14767058.2010.538454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Wagner CL, et al. Vitamin d and its role during pregnancy in attaining optimal health of mother and fetus. Nutrients. 2012;4(3):208–230. doi: 10.3390/nu4030208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Disanto G, et al. Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Human Molecular Genetics. 2012;21(16):3575–3586. doi: 10.1093/hmg/dds189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Buratti E, Baralle FE. The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation. RNA Biology. 2010;7(4):420–429. doi: 10.4161/rna.7.4.12205. [DOI] [PubMed] [Google Scholar]
  • 89.Trabucchi M, et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature. 2009;459(7249):1010–1014. doi: 10.1038/nature08025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Iorio MV, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Research. 2005;65(16):7065–7070. doi: 10.1158/0008-5472.CAN-05-1783. [DOI] [PubMed] [Google Scholar]
  • 91.Yanaihara N, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. CancerCell. 2006;9(3):189–198. doi: 10.1016/j.ccr.2006.01.025. [DOI] [PubMed] [Google Scholar]
  • 92.Mohri T, Nakajima M, Takagi S, Komagata S, Yokoi T. MicroRNA regulates human vitamin D receptor. Int J Cancer. 2009;125(6):1328–1333. doi: 10.1002/ijc.24459. [DOI] [PubMed] [Google Scholar]
  • 93.Giangreco AA, Vaishnav A, Wagner D, Van der Kwast T, Vieth R, Nonn L. Tumor suppressor microRNAs, miR-100 and -125b, are regulated by 1,25– dihydroxyvitamin D in primary prostate cells and in patient tissue. Cancer Prevention Research. 2013 doi: 10.1158/1940-6207.CAPR-12-0253. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]

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