Table 2 Evidence of specific functional relationships between the vitamin D / Vitamin D Receptor (VDR) pathway and long noncoding RNAs (lncRNAs)
From: Tracing vitamins on the long non-coding lane of the transcriptome: vitamin regulation of LncRNAs
Compound | LncRNA(s) studied in the project | System: Patients / cell line(s) / animal model | Highlighted lncRNA(s)/ pathway(s)/ target(s)/ partners/ interactions | Disease context/ implication for human disease | Main result(s) | Ref |
|---|---|---|---|---|---|---|
Cancer | ||||||
Vitamin D | AS-HSD17β2 (RP11 510J16.5) | Human keratinocyte cell line: (HaCaT) Human prostate cancer cell lines: PC3, LNCaP, CWR22 | HSD17β2/ AS-HSD17β2 (Hydroxysteroid 17-Beta Dehydrogenase 2) | Prostate cancer | AS-HSD17β2 is a potential directly regulated target of vitamin D. It attenuates HSD17β2 expression, HSD17β2is involved in the VDR pathway and steroid metabolism | [40] |
LUCAT1 | human oral squamous cell carcinoma (OSCC) cell lines: CAL27 and SCC9 OSCC patient tumor samples and adjacent noncancerous (ANC) samples | LUCAT1-MAPK signaling pathway | Oral squamous cell carcinoma (OSCC) | Through the MAPK pathway, vitamin D suppresses the growth of oral squamous cell carcinoma by inhibiting the lncRNA LUCAT1 This study helps to mechanistically explain how vitamin D may suppress the progression of oral cancer | [44] | |
lncBCAS1-4_1 | Human ovarian cancer cell line SKOV3 | Link between EMT and vitamin D signaling via the lncBCAS1-4_1-lncRNA | Ovarian cancer | In a study of 1α,25(OH)2D3 impact on expression of lncRNAs, lncBCAS1-4_1 suggested a link of vitamin D signaling and EMT | [42] | |
CCAT2 | The epithelial ovarian carcinoma (EOC) cell lines SKOV3 and A2780 | VitD/CCAT2 axis | Ovarian Cancer | Vitamin D inhibits ovarian cancer cell growth via downregulation of lncRNA CCAT2 | [53] | |
MEG3 | 371 colorectal cancer patients who underwent curative resection RKO, SW1116, HT29, HCT116, LoVo, SW620, SW480 and 293T | VDR/MEG3/Clusterin | Colorectal cancer (CRC) | • Down-regulation of MEG3 was observed in CRC tissues and associated with poor prognosis • MEG3 may act through the VDR/MEG3/Clusterin pathway MEG3 inhibited CRC metastasis and proliferation | [45] | |
lnc-CYP24A1-3:1, and lnc-TSHZ2-19:1 (Novel lncRNAs related to CYP24A1 and PFDN4 genes in colorectal cancer (CRC)) | Colon cancer cell lines: HCT-116 and HT-29 | CYP24A1 | Colorectal Cancer (CRC) | CYP24A1, PFDN4, lnc-CYP24A1-3:1, and lnc-TSHZ2-19:1 are putative novel diagnostic markers for CRC. Vitamin D regulates expression of these genes | [54] | |
MEG3 | 80 CRC samples and corresponding adjacent normal mucosal samples human CRC cell lines: DLD-1 and RKO | Vitamin D/MEG3/ c-myc | Colorectal cancer (CRC) | Vitamin D-activated long non-coding RNA MEG3 suppresses glycolysis in CRC by enhancing c-Myc degradation | [55] | |
H19 | Human cell lines: SH‐SY5Y and SNB‐19 cells Rat brain tissues | H19/miR-675/vitamin D receptor (VDR) | Glioma | • A negative feedback loop of H19/miR-675/VDR has been shown in the development of glioma • The effect of [curcumin and also] 1,25(OH2 D3) was assessed | [56] | |
H19 | PBMCs of newly diagnosed ALL patients (For gene expression analysis) & Serum (for 25-hydroxy vitamin D measurement) | _ | Acute Lymphoblastic Leukemia (ALL) | Gene expression analysis showed concurrent downregulation of VDR and H19 expression in ALL patients vs control group (potential implication for H19 as both a biomarker and a functional contributor) | [57] | |
VDR | H19 | Patients with colon cancer Cell lines: HT-29 and DLD-1 | VDR/H19/miR-675-5p | Colon cancer | Overexpression of H19 increases resistance to 1,25(OH)2D3 by downregulation of VDR through miR-675-5p. VDR signaling may suppress H19 via the C-Myc/Mad-1 network | [41] |
TOPORS-AS1 | Fresh tumor samples of 266 patients with ovarian cancer Six ovarian cancer cell lines: (IGROV1, SKOV3, OVCAR3, OVCAR4, OVCAR5, OVCAR8) | Wnt/β-catenin pathway | Ovarian cancer | The lncRNA TOPORS-AS1 was highlighted as a potential tumor suppressor by interruption of the Wnt/β-catenin signaling. VDR could positively regulate TOPORS-AS1 | [43] | |
LINC00346; LINC00511; MALAT1; SNHG16; SNHG6 | 75 breast tumor samples (invasive ductal carcinoma of breast) and their adjacent noncancerous tissues (ANCTs) | _ | Breast cancer | • VDR, MALAT1, and LINC00511 were upregulated in tumors vs. ANCT • SNHG16 and LINC00511 expression levels correlated with nuclear grade. LINC00346 level correlated with tubule formation. SNHG16 and SNHG6 expression levels correlated with family history of cancer. VDR expression correlated with progesterone receptor status • FOKI polymorphism was associated with over-expression of VDR • FOKI variants were associated with expression levels of MALAT1 and SNHG16 in non-cancerous tissues • CDX2 variants were associated with expression levels of SNHG16 in ANCTs. SNHG16 expression significantly correlated with vitamin D levels | [48] | |
MALAT1 | Computational identification of lncRNAs that modulate VDR signaling in BC | _ | Breast cancer | • MALAT1 was among lncRNAs inferred to affect VDR signaling in BC | [58] | |
MALAT1, SNHG16, SNHG6, LINC00346, LINC00511 | 32 pairs of lung cancer tissues and adjacent non-cancerous tissues (ANCTs) | LINC00346 SNHG6 | Lung cancer | • VDR and LINC00346 were downregulated in male tumor tissues vs matched ANCT | [59] | |
Neurological and brain disorders | ||||||
Vitamin D | HOTAIR | 42 patients with relapsing–remitting MS Cell line: THP-1 cells | _ | Multiple Sclerosis | The lncRNA HOTAIR was overexpressed in the PBMCs of MS patients with VD-deficiency compared with healthy controls | [47] |
LncRNAs previously known to be relevant to VDR (LINC00511, LINC00346, SNHG6 and SNHG16) | Peripheral blood of 40 epileptic patients and 39 healthy subjects | _ | Epilepsy | • Expression of VDR-related lncRNAs (including LINC00511, LINC00346, SNHG6, and SNHG16) was assessed in epileptic patients • SNHG16 was upregulated in male patients vs. male controls • LINC00511 was upregulated in female patients vs. female control • Significant association of SNHG6 and SNHG16 expression with gender • Significantly co-expressed correlated gene pairs were found: [SNHG6 and SNHG16], [SNHG6 and LINC00346], [SNHG16 and LINC00346], [SNHG16 and LINC00511] • Inverse correlation between expression of LINC00346 and vitamin D levels only in male epileptic patients | [52] | |
VDR | SNHG6, SNHG16, LINC00346 | Parkinson's disease patients | _ | Parkinson's disease (PD) | • Expression of VDR and SNHG6, SNHG16, and LINC00346 was assessed in PD • SNHG6 and VDR differentiate PD patients from controls | [49] |
VDR-associated lncRNAs (SNHG6, CYP27B1, MALAT1, Linc00346, LINC00511) | Peripheral blood of BD patients vs. healthy individuals | _ | Bipolar disorder (BD) | • Upregulation of SNHG6, CYP27B1, MALAT1, Linc00346, and VDR in total BP patients vs. control groups • Upregulation of SNHG6, CYP27B1, MALAT1, Linc00346, VDR in BP males vs. normal male controls • Upregulation of SNHG6 in BP females. vs. normal female controls • These VDR-associated lncRNAs are possible biomarkers for BD and should be investigated for causality in its etiology | [50] | |
SNHG6, LINC00346, LINC00511 | Peripheral blood of schizophrenia patients vs. healthy individuals | _ | Schizophrenia (SCZ) | • Upregulation of SNHG6 and LINC00346in SCZ patients vs. controls • These VDR-associated lncRNAs are possible biomarkers for SZ and should be investigated for causality in its etiology | [51] | |
SNHG6 and LINC00511 | Circulating blood transcriptome of ASD patients compared with normal controls | _ | Autism Spectrum Disorder (ASD) | Gene expression assessment of VDR, CYP27B1, SNHG6, and LINC00511 showed upregulation of CYP27B1 & downregulation of in ASD patients vs controls, implying a role in ASD | [60] | |
Cardiovascular diseases | ||||||
Vitamin D | MALAT1 | PBMCs of coronary artery disease (CAD) patients & non-CAD (NCAD) participants | Expression correlation between MALAT1/CD36/IL-22 | Coronary Artery Disease (CAD) | A significant correlation was found, implying a protective role of vitamin D against vascular complications in CAD | [46] |
VDR | H19 | Infarcted heart tissue of H19 KO mice | H19-VDR axis | Myocardial ischemia | Investigation of the role of H19 in myocardial infarction in vivo and under oxygen deficiency in vitro showed that H19 regulates cardiomyocyte apoptosis and cardiac inflammation through the VDR pathway | [61] |
Diabetes | ||||||
Vitamin D | _ | Endothelial Progenitor Cells (EPCs) and control cells from bone marrow (BM) | _ | Endothelial cell function in type 2 diabetes mellitus (T2D) | 1,25(OH)2D3 enhances endothelial progenitor cell (EPC) function through a competing endogenous RNA (ceRNA) network | [62] |
LINC01173 | 200 newly diagnosed untreated T2DM and 200 healthy controls | _ | Type 2 diabetes mellitus (T2DM) | Overexpression of lncRNA LINC01173 in the blood of vitamin-D deficient T2DM cases was significant compared to insufficient and sufficient T2DM groups | [63] | |
VDR | H19 | Human subjects: Renal tissues of 54 Diabetes Mellitus patients [29 DM patients with diabetic nephropathy (DN) and 25 without DN] Cell lines: CIHP-1/HEK 293 cells | H19/miR-675/EGR1 | Diabetic Nephropathy (DN) | An inhibitory loop including H19, miR‐675, VDR, and EGR1 was demonstrated in the pathological mechanism of DN | [64] |
Other pathologies | ||||||
VDR | H19 | Peripheral Blood Mononuclear Cells (PBMCs) of AS [5 AS patients and 5 healthy controls (HCs)] | H19-miR22-5p/miR675-5p-VDR-IL-17A/IL-23 signaling | Ankylosing Spondylitis (AS) | H19-miR22-5p/miR675-5p-VDR-IL-17A/IL-23 signaling pathways are implicated in the pathogenesis of AS | [65] |
Differential expression analysis of miRNAs, lncRNAs, and mRNAs (Microarray analysis) | Sprague Dawley rats | miR-98/VDR 5 lncRNAs (NR_046246.1, NR_046239.1, XR_086062.1, XR_145872.1 and XR_146737.1), may play important roles in regulating the CN-induced osteogenic differentiation of MSCs | Mesenchymal Stem Cells (MSCs) osteogenic differentiation | To interrogate the role of ( +)-cholesten-3-one (CN) in osteoblastic differentiation of (MSCs), DE analysis was performed and showed enrichment in the VDR pathway. Key finding: miR-298 could enhance the osteogenic differentiation of MSCs via the VDR pathway | [66] | |
SNHG6, SNHG16 | Peripheral blood | _ | COVID -19 | Expression assessment of VDR, VDR-associated lncRNAs (including SNHG16, SNHG6, LINC00346, and LINC00511), and CYP27B1 in COVID-19 patients versus healthy subjects showed plausible joint roles of SNHG16 and VDR inCOVID-19 infection | [67] | |