Unknown,Transcriptomics,Genomics,Proteomics

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Vitamin D receptor expression and associated gene signature in tumor stromal fibroblasts predict clinical outcome in colorectal cancer

ABSTRACT: Colorectal cancer (CRC) is a major cause of cancer mortality and a serious health concern worldwide. Vitamin D deficiency is associated with high CRC incidence and mortality, suggesting a protective effect of vitamin D against this neoplasia. Although the antiproliferative and prodifferentiation action of active vitamin D (1alpha,25-dihydroxyvitamin D3, 1,25(OH)2D3) on colon carcinoma cells is well documented, its potential effects on CRC stroma are unknown. Here, we show that high vitamin D receptor (VDR) expression in tumor stromal fibroblasts is associated with better overall and progression-free survival in a large cohort of CRC patients, irrespective of its expression in carcinoma cells. Consistently, 1,25(OH)2D3 inhibits the activation of patient-derived normal and cancer-associated fibroblasts, and their pro-migratory effect on carcinoma cells. Importantly, we show by global transcriptomic analyses that 1,25(OH)2D3 regulates cancer-associated fibroblast gene expression and imposes a gene signature that is associated with longer overall and disease-free survival of CRC patients. Moreover, expression of two genes from the signature, CD82 and S100A4, correlates with stromal VDR expression and clinical outcome in CRC. This study provides the first evidence that vitamin D has protective effects against CRC through the regulation of stromal fibroblasts. Characterization of 1,25(OH)2D3 action on gene expression in primary cultures of colon normal and tumor fibroblasts established from samples from colorectal cancer patients. RNA from seven paired normal and tumor fibroblast primary cultures treated with 1,25(OH)2D3 or vehicle for 48 h were analyzed.

ORGANISM(S): Homo sapiens

SUBMITTER: Maria Larriba

PROVIDER: E-GEOD-70468 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2 plays a pivotal role in vitamin D receptor (VDR) signaling by acting as a vitamin D response element (VDRE)-binding protein (VDRE-BP). Transcriptional regulation by active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) involves occupancy of VDRE by VDRE-BP or 1,25(OH)2D3 bound-VDR. This relationship is disrupted by over-expression of VDRE-BP and can cause a form of human hereditary vitamin D-resistant rickets (HVDRR). DNA array analyses using B-cells from an HVDRR patient and matched control defined a sub-cluster of genes where 1,25(OH)2D3-regulated transcription was abrogated by over-expression of VDRE-BP. Amongst these, the DNA-damage-inducible transcript 4 (DDIT4), an inhibitor of mammalian target of rapamycin (mTOR) signaling, was also induced by 1,25(OH)2D3 in human osteoblasts. Chromatin immunoprecipitation using 1,25(OH)2D3-treated osteoblasts confirmed that liganded VDR and VDRE-BP compete for binding to the proximal promoter of the DDIT4 gene in a similar fashion to other known 1,25(OH)2D3-target genes. Treatment of osteoblasts with 1,25(OH)2D3 induced DDIT4 expression and suppressed phosphorylated S6K1T389 protein (a downstream target of mTOR). The functional importance of this for 1,25(OH)2D3 responses in osteoblasts was underlined by the fact that siRNA knockdown of DDIT4 expression suppressed antiproliferative and cell growth responses to 1,25(OH)2D3. These data confirm that VDRE-BP is required for normal 1,25(OH)2D3-mediated transcription and cell function in osteoblasts. Conversely over-expression of VDRE-BP exerts a dominant-negative effect on transcription of 1,25(OH)2D3-target genes. Characterization of VDRE-BP action in 1,25(OH)2D3-treated osteoblasts highlights an entirely novel role for vitamin D as a regulator of mTOR – a known ‘master regulator’ of cell function. We performed gene expression microarray analysis in HVDRR EBV-transformed B-cells and control cells in the presence or absence of vitamin D.

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Vitamin D receptor expression and associated gene signature in tumor stromal fibroblasts predict clinical outcome in colorectal cancer

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