Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
No abstract
Mutations in the gene encoding collagen VII (C7) cause the devastating blistering disease recessive dystrophic epidermolysis bullosa (RDEB). This disease is characterized by severe skin fragility and non-healing wounds aggravated by scarring and fibrosis. The altered skin architecture in RDEB also allows for development of fatal squamous cell carcinoma. We previously demonstrated that the matricellular protein thrombospondin-1 (TSP1) is increased in RDEB fibroblasts and that C7 expression modulates TSP1. Because TGF-beta is increased in RDEB and correlates with disease severity, and TSP1 is shown to activate TGF-beta, we investigated the role of TSP1 in TGF-beta activation in RDEB patient cells. Knock-down of TSP1 reduced phosphorylation of SMAD3 (a downstream target of TGF-beta signaling) in RDEB patient fibroblasts. In contrast, no reduced SMAD3 phosphorylation was observed in control cells. Over-expression of C7 in RDEB fibroblasts reduced TSP1 and phosphorylation of SMAD3. Furthermore, inhibition of TSP1 binding to the latency-associated protein (LAP)/ TGF-beta complex decreased fibrosis in engineered extracellular matrix derived from RDEB fibroblasts, as evaluated by picrosirius red staining and analyses of birefringent collagen fibrillar deposits. Using immuno-precipitation, proximity ligation assay and real-time, labelfree analysis of binding interactions, we demonstrate that C7 binds TSP1, thereby likely preventing TSP1-LAP association and subsequent TGF-beta activation. Our study suggests a novel mechanism for increased TGF-beta signaling in the absence of C7 in RDEB patient skin. Moreover, our data identify TSP1 as a possible target for reducing fibrosis in the tumor-promoting dermal microenvironment in RDEB patients.
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