scholarly journals Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
P. G. Vaughan-Shaw ◽  
G. Grimes ◽  
J. P. Blackmur ◽  
M. Timofeeva ◽  
M. Walker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Expression Patterns ◽  
Rectal Mucosa ◽  
Vitamin D Supplementation ◽  
Gene Expression Patterns ◽  
Blood Biomarkers ◽  
Oral Vitamin ◽  
Gene Set ◽  
Transcriptomic Changes

Abstract Background The risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response. Methods Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D). Results Six hundred twenty-nine genes were associated with 25-OHD level (P < 0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P < 1.0E−07; downregulated gene-set P < 2.6E−05) and corresponding GO terms (P = 2.90E−02), highlighting gene expression patterns consistent with anti-tumour effects. However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P < 0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI 0.66–1.00]) and replicated in BEST-D trial subjects (HIPK2 AUC=0.83 [95%CI 0.77–0.89]; PPP1CC AUC=0.91 [95%CI 0.86–0.95]). Conclusions Higher plasma 25-OHD correlates with rectal mucosa gene expression patterns consistent with anti-tumour effects, and this beneficial signature is induced by short-term vitamin D supplementation. Heterogenous gene expression responses to vitamin D may limit the ability of randomised trials to identify beneficial effects of supplementation on CRC risk. However, in the current study blood expression changes in HIPK2 and PPP1CC identify those participants with significant anti-tumour transcriptomic responses to supplementation in the rectum. These data provide compelling rationale for a trial of vitamin D and CRC prevention using easily assayed blood gene expression signatures as intermediate biomarkers of response.

scholarly journals Oral Vitamin D supplementation induces transcriptomic changes in rectal mucosa that are consistent with anti-tumour effects.

2021 ◽  
Author(s):  
Peter G Vaughan-Shaw ◽  
Graeme Grimes ◽  
James P Blackmur ◽  
Maria Timofeeva ◽  
Marion Walker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Expression Patterns ◽  
Rectal Mucosa ◽  
Vitamin D Supplementation ◽  
Gene Expression Patterns ◽  
Blood Biomarkers ◽  
Oral Vitamin ◽  
Gene Set ◽  
Transcriptomic Changes

Background Risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in-vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response. Methods Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D). Results 629 genes were associated with 25-OHD level (P<0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P<1.0E-07; downregulated gene-set P<2.6E-05) and corresponding GO terms (P=2.90E-02), highlighting gene expression patterns consistent with anti-tumour effects. However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P<0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI:0.66-1.00]), and replicated in BEST-D trial subjects (HIPK2 AUC=0.83 [95%CI:0.77-0.89]; PPP1CC AUC=0.91 [95%CI:0.86-0.95]). Conclusions Higher plasma 25-OHD correlates with rectal mucosa gene expression patterns consistent with anti-tumour effects and this beneficial signature is induced by short-term vitamin D supplementation. Heterogenous gene expression responses to vitamin D may limit the ability of randomised trials to identify beneficial effects of supplementation on CRC risk. However, in the current study blood expression changes in HIPK2 and PPP1CC identify those participants with significant anti-tumor transcriptomic responses to supplementation in the rectum. These data provide compelling rationale for a trial of vitamin D and CRC prevention using easily assayed blood gene expression signatures as intermediate biomarkers of response.

Gene set based systematic analysis of prostate cancer and its subtypes

2020 ◽  
Vol 16 (2) ◽  
pp. 4381-4393
Author(s):  
Senlin Ye ◽  
Haohui Wang ◽  
Kancheng He ◽  
Hongwei Shen ◽  
Mou Peng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Expression Patterns ◽  
Methylation Status ◽  
Gene Expression Patterns ◽  
Biological Functions ◽  
Systematic Analysis ◽  
Gene Set ◽  
Analysis Strategy ◽  
Similarities And Differences

Aim: A gene set based systematic analysis strategy is used to investigate prostate tumors and its subclusters with focuses on similarities and differences of biological functions. Results: Dysregulation of methylation status, as well as RAS/RAF/ERK and PI3K-ATK signaling pathways, were found to be the most dramatic changes during prostate cancer tumorigenesis. Besides, neural and inflammation microenvironment is also significantly divergent between tumor and adjacent tissues. Insights of subclasses within prostate tumor cohorts revealed four different clusters with distinct gene expression patterns. We found that samples are mainly clustered by immune environments and proliferation traits. Conclusion: The findings of this article may help to advance the progress of identifying better diagnosis biomarkers and therapeutic targets.

scholarly journals Comparative Study of Organoids from Patient-Derived Normal and Tumor Colon and Rectal Tissue

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2302 ◽  
Author(s):  
Alba Costales-Carrera ◽  
Asunción Fernández-Barral ◽  
Pilar Bustamante-Madrid ◽  
Orlando Domínguez ◽  
Laura Guerra-Pastrián ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Gene Expression Profile ◽  
Expression Patterns ◽  
Rectal Tumor ◽  
Gene Expression Patterns ◽  
Rectal Tumors ◽  
Normal Colon ◽  
Colon And Rectum ◽  
Tumor Organoids

Colon and rectal tumors, often referred to as colorectal cancer, show different gene expression patterns in studies that analyze whole tissue biopsies containing a mix of tumor and non-tumor cells. To better characterize colon and rectal tumors, we investigated the gene expression profile of organoids generated from endoscopic biopsies of rectal tumors and adjacent normal colon and rectum mucosa from therapy-naive rectal cancer patients. We also studied the effect of vitamin D on these organoid types. Gene profiling was performed by RNA-sequencing. Organoids from a normal colon and rectum had a shared gene expression profile that profoundly differed from that of rectal tumor organoids. We identified a group of genes of the biosynthetic machinery as rectal tumor organoid-specific, including those encoding the RNA polymerase II subunits POLR2H and POLR2J. The active vitamin D metabolite 1α,25-dihydroxyvitamin D3/calcitriol upregulated stemness-related genes (LGR5, LRIG1, SMOC2, and MSI1) in normal rectum organoids, while it downregulated differentiation marker genes (TFF2 and MUC2). Normal colon and rectum organoids share similar gene expression patterns and respond similarly to calcitriol. Rectal tumor organoids display distinct and heterogeneous gene expression profiles, with differences with respect to those of colon tumor organoids, and respond differently to calcitriol than normal rectum organoids.

scholarly journals Gene Co-Expression Network Analysis Identifies Vitamin D-Associated Gene Modules in Adult Normal Rectal Epithelium Following Supplementation

2022 ◽  
Vol 12 ◽  
Author(s):  
James P. Blackmur ◽  
Peter G. Vaughan-Shaw ◽  
Kevin Donnelly ◽  
Bradley T. Harris ◽  
Victoria Svinti ◽  
...  
Keyword(s):  
Vitamin D ◽  
Network Analysis ◽  
Expression Patterns ◽  
Rectal Mucosa ◽  
Vitamin D Supplementation ◽  
Plasma Vitamin ◽  
Target Tissue ◽  
Hub Genes ◽  
Gene Modules

Colorectal cancer (CRC) is a common, multifactorial disease. While observational studies have identified an association between lower vitamin D and higher CRC risk, supplementation trials have been inconclusive and the mechanisms by which vitamin D may modulate CRC risk are not well understood. We sought to perform a weighted gene co-expression network analysis (WGCNA) to identify modules present after vitamin D supplementation (when plasma vitamin D level was sufficient) which were absent before supplementation, and then to identify influential genes in those modules. The transcriptome from normal rectal mucosa biopsies of 49 individuals free from CRC were assessed before and after 12 weeks of 3200IU/day vitamin D (Fultium-D3) supplementation using paired-end total RNAseq. While the effects on expression patterns following vitamin D supplementation were subtle, WGCNA identified highly correlated genes forming gene modules. Four of the 17 modules identified in the post-vitamin D network were not preserved in the pre-vitamin D network, shedding new light on the biochemical impact of supplementation. These modules were enriched for GO terms related to the immune system, hormone metabolism, cell growth and RNA metabolism. Across the four treatment-associated modules, 51 hub genes were identified, with enrichment of 40 different transcription factor motifs in promoter regions of those genes, including VDR:RXR. Six of the hub genes were nominally differentially expressed in studies of vitamin D effects on adult normal mucosa organoids: LCN2, HLA-C, AIF1L, PTPRU, PDE4B and IFI6. By taking a gene-correlation network approach, we have described vitamin D induced changes to gene modules in normal human rectal epithelium in vivo, the target tissue from which CRC develops.

Gene expression analysis suggests that 1,25-dihydroxyvitamin D3reverses experimental autoimmune encephalomyelitis by stimulating inflammatory cell apoptosis

2004 ◽  
Vol 18 (2) ◽  
pp. 141-151 ◽  
Author(s):  
Karen M. Spach ◽  
Laura B. Pedersen ◽  
Faye E. Nashold ◽  
Tsuyoshi Kayo ◽  
Brian S. Yandell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Expression Patterns ◽  
Initiation Factor ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Gene Expression Patterns ◽  
Autoimmune Encephalomyelitis ◽  
Biological Studies ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (CNS) that develops in genetically susceptible individuals who are exposed to undefined environmental risk factors. Epidemiological, genetic, and biological evidence suggests that insufficient vitamin D may be an MS risk factor. However, little is known about how vitamin D might be protective in MS. We hypothesized that 1,25-dihydroxyvitamin D3[1,25-(OH)2D3] might regulate gene expression patterns in a manner that would resolve inflammation. To test this hypothesis, experimental autoimmune encephalomyelitis (EAE) was induced in mice, 1,25-(OH)2D3or a placebo was administered, and 6 h later, DNA microarray hybridization was performed with spinal cord RNA to analyze the gene expression patterns. At this time, clinical, histopathological, and biological studies showed that the two groups did not differ in EAE disease, but changes in several 1,25-(OH)2D3-responsive genes indicated that the 1,25-(OH)2D3had reached the CNS. Compared with normal mice, placebo-treated mice with EAE showed increased expression of many immune system genes, confirming the acute inflammation. When 1,25-(OH)2D3was administered, several genes like glial fibrillary acidic protein and eukaryotic initiation factor 2α kinase 4, whose expression increased or decreased with EAE, returned to homeostatic levels. Also, two genes with pro-apoptotic functions, calpain-2 and caspase-8-associated protein, increased significantly. A terminal deoxynucleotidyl transferase-mediated dUTP nicked end labeling study detected increased nuclear fragmentation in the 1,25-(OH)2D3-treated samples, confirming increased apoptosis. Together, these results suggest that sensitization of inflammatory cells to apoptotic signals may be one mechanism by which the 1,25-(OH)2D3resolved EAE.

Prediction of metastatic behavior in high-grade pleomorphic soft tissue sarcomas by gene expression.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10561-10561
Author(s):  
Keith M. Skubitz ◽  
Amy Skubitz ◽  
Wayne Xu ◽  
Xianghua Luo ◽  
Pauline Lagarde ◽  
...  
Keyword(s):  
Gene Expression ◽  
Soft Tissue ◽  
Expression Patterns ◽  
Soft Tissue Sarcomas ◽  
Gene Expression Patterns ◽  
High Grade ◽  
Data Set ◽  
Gene Set ◽  
Kaplan Meier ◽  
Gene Sets

10561 Background: The biologic heterogeneity of soft tissue sarcomas (STS) complicates treatment. Metastatic propensity may be determined by gene expression patterns that do not correlate well with morphology. In earlier studies, gene expression patterns were identified that distinguish 2 subsets of clear cell renal carcinoma (RCC), serous ovarian carcinoma (OVCA), and aggressive fibromatosis (AF). We reported the use of a gene set derived from these three studies to separate 73 high grade STS into groups with different probabilities of developing metastatic disease (PrMet). We wished to confirm our findings using an independent data set. Methods: We utilized these gene sets, hierarchical clustering (HC), Kaplan-Meier, and log-rank analyses to examine the Affymetrix HU_133 expression profiles of 309 STS. Results: HC using a pooled gene set derived from the AF-, RCC-, and OVCA-gene sets identified subsets of the STS samples. Kaplan-Meier analysis revealed differences in PrMet between the clusters defined by the first branch point of the clustering dendrogram (p=0.048), and also among the 4 different clusters defined by the second branch points (p<0.0001). Analysis also revealed differences in PrMet between the leiomyosarcomas (LMS), dedifferentiated liposarcomas (LipoD), and undifferentiated pleomorphic sarcomas (UDS) (p=0.0004). HC of the LipoD and UDS samples with the pooled probe set divided the samples into 2 groups with different PrMet (p=0.013, and 0.0002, respectively). HC of the UDS samples also showed 4 groups with different PrMet (p=0.0007). In contrast, HC found no subgroups of the LMS samples. Each individual gene set (AF-, RCC-, and OVCA-) separated the UDS samples into subsets of different metastatic outcome, but only the AF- gene set separated the LipoD samples, and no gene set identified LMS subsets. Conclusions: These data confirm our earlier studies and suggest that this approach may allow the identification of more than 2 subsets of high grade STS, each with distinct clinical behavior, and may be useful to stratify STS in clinical trials and in patient management.

scholarly journals Mice lacking uterine enhancer of zeste homolog 2 have transcriptomic changes associated with uterine epithelial proliferation

2020 ◽  
Vol 52 (2) ◽  
pp. 81-95 ◽  
Author(s):  
Ana M. Mesa ◽  
Jiude Mao ◽  
Manjunatha K. Nanjappa ◽  
Theresa I. Medrano ◽  
Sergei Tevosian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Null Model ◽  
Conditional Knockout ◽  
Gene Expression Patterns ◽  
Hippo Signaling ◽  
Rna Seq ◽  
Epithelial Proliferation ◽  
Enhancer Of Zeste ◽  
Transcriptomic Changes

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that suppresses gene expression. Previously, we developed a conditional null model where EZH2 is knocked out in uterus. Deletion of uterine EZH2 increased proliferation of luminal and glandular epithelial cells. Herein, we used RNA-Seq in wild-type (WT) and EZH2 conditional knockout ( Ezh2cKO) uteri to obtain mechanistic insights into the gene expression changes that underpin the pathogenesis observed in these mice. Ovariectomized adult Ezh2cKO mice were treated with vehicle (V) or 17β-estradiol (E2; 1 ng/g). Uteri were collected at postnatal day (PND) 75 for RNA-Seq or immunostaining for epithelial proliferation. Weighted gene coexpression network analysis was used to link uterine gene expression patterns and epithelial proliferation. In V-treated mice, 88 transcripts were differentially expressed (DEG) in Ezh2cKO mice, and Bmp5, Crabp2, Lgr5, and Sprr2f were upregulated. E2 treatment resulted in 40 DEG with Krt5, Krt15, Olig3, Crabp1, and Serpinb7 upregulated in Ezh2cKO compared with control mice. Transcript analysis relative to proliferation rates revealed two module eigengenes correlated with epithelial proliferation in WT V vs. Ezh2cKO V and WT E2 vs. Ezh2cKO E2 mice, with a positive relationship in the former and inverse in the latter. Notably, the ESR1, Wnt, and Hippo signaling pathways were among those functionally enriched in Ezh2cKO females. Current results reveal unique gene expression patterns in Ezh2cKO uterus and provide insight into how loss of this critical epigenetic regulator assumingly contributes to uterine abnormalities.

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