Abstract
Cripto, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-β, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. Cripto is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the CRIPTO gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides CRIPTO, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5’UTR of CRIPTO gene which is able to strongly modulate CRIPTO expression through an AP-1-mediate transcriptional regulation.
Highlights
Cripto, known as Teratocarcinoma-derived growth factor 1 (TDGF1), is the original member of the Epidermal Growth Factor-Cripto/Fibroblast growth factor Receptor Ligand 1/Cryptic (EGF-CFC) family of vertebrate proteins involved in embryo development [1,2,3]
Cripto gene has a fundamental role in embryo development and is involved in cancer
CRIPTO is detected at very low levels in normal tissues and in the blood, while its increase in both tissues and blood is associated to pathological conditions, mainly cancer
Summary
Known as Teratocarcinoma-derived growth factor 1 (TDGF1), is the original member of the Epidermal Growth Factor-Cripto/Fibroblast growth factor Receptor Ligand 1/Cryptic (EGF-CFC) family of vertebrate proteins involved in embryo development [1,2,3]. Cripto has been isolated in human and mouse [3] and is a GPI-anchored membrane protein [4] that can function in both membrane anchored and soluble form [5,6]. It is involved in multiple signaling pathways, such as TGF-β, Wnt and MAPK/ERK pathways, it regulates essential steps in early embryogenesis and it is involved in processes such as cell migration, epithelial-mesenchymal transition (EMT), stem cell maintenance, all processes which are implicated in cancerogenesis [7,8,9,10,11,12,13,14]. In vitro and in vivo functional studies confirm a strong involvement of Cripto in cancer development and indicate that its effect on tumorigenesis might strictly depend on the cellular context in which it acts [28,29,30,31,32,33]
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