Down Syndrome Expressed Protein; DSCR-1 Deters Cancer and Septic Inflammation

Abstract

Down syndrome is the most common genetic cause of mental retardation in humans, occurring in one out of 700 live births. Epidemiological studies suggest that although individuals with Down syndrome have an increased risk of infant cardiovascular malformation, muscle hypotonia, lymphatic edema, and leukemia, noteworthy they have a considerably reduced incidence of most solid tumor, atherosclerosis, and pathological angiogenesis-mediated diabetic retinopathy and kidney dysfunction. Such data indicate that one or more of the 231 trisomic genes on chromosome 21 are responsible for protecting these individuals against cancer and vascular disease. We and others recently have identified the candidate genes are Down syndrome critical region (DSCR)-1, and A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-1. In primary cultured endothelial cells, vascular endothelial cell growth factor (VEGF) resulted in rapid and profound upregulation of both genes, which in turn negatively feeds back to attenuate VEGF-mediated signaling and following the endothelial cell activation. In genome-wide screening, important regulatory transcription factor for many pathological features of Down syndrome, NFAT, bound more than 10,000 independent regions in VEGF-treated activated endothelial cells. Down syndrome trisomy model mice or endothelium-specific modest DSCR-1 increases in mice resulted in significant suppression of the vascular density in matrigel-plugs, inflammatory leukocyte infiltration, and tumor growth. In contrast, DSCR-1 null mice demonstrated markedly decreased vascular integrity and increased susceptibility to tumor metastasis. In a mouse model of endotoxemia, DSCR-1 null mice showed greater morbidity and mortality compared with wild-type littermate. Conversely, adenovirus-mediated overexpression of DSCR-1 resulted in marked attenuation of lipopolysaccharide (LPS) or VEGF-mediated inflammation. Collectively, these data provide that Down syndrome overexpressed protein; DSCR-1 serves to dampen the host response to infection and the tumor growth. The molecular research for Down syndrome with patients or model mice unexpectedly provide us a great hint for therapeutic targets in solid tumor and vasculopathic disease against all individuals.