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Background  Human Hematopoietic Signal peptide-containing Secreted 1 ( h HSS1) is a truly novel protein, defining a new class of secreted factors. We have previously reported that ectopic overexpression of  h HSS1 has a negative modulatory effect on cell proliferation and tumorigenesis in glioblastoma model systems. Here we have used microarray analysis, screened glioblastoma samples in The Cancer Genome Atlas (TCGA), and studied the effects of  h HSS1 on glioma-derived cells and endothelial cells to elucidate the molecular mechanisms underlying the anti-tumorigenic effects of  h HSS1.    Methods  Gene expression profiling of human glioma U87 and A172 cells overexpressing  h HSS1 was performed. Ingenuity® iReport™ and Ingenuity Pathway Analysis (IPA) were used to analyze the gene expression in the glioma cells. DNA content and cell cycle analysis were performed by FACS, while cell migration, cell invasion, and effects of  h HSS1 on HUVEC tube formation were determined by transwell and matrigel assays. Correlation was made between  h HSS1 expression and specific genes in glioblastoma samples in the TCGA database.    Results  We have clarified the signaling and metabolic pathways (i.e. role of BRCA1 in DNA damage response), networks (i.e. cell cycle) and biological processes (i.e. cell division process of chromosomes) that result from  h HSS1effects upon glioblastoma growth. U87-overexpressing  h HSS1 significantly decreased the number of cells in the G0/G1 cell cycle phase, and significantly increased cells in the S and G2/M phases ( P  < 0.05). U87-overexpressing  h HSS1 significantly lost their ability to migrate ( P  < 0.001) and to invade ( P  < 0.01) through matrigel matrix.  h HSS1-overexpression significantly decreased migration of A172 cells ( P  < 0.001), inhibited A172 tumor-induced migration and invasion of HUVECs ( P  < 0.001), and significantly inhibited U87 tumor-induced invasion of HUVECs ( P  < 0.001). Purified  h HSS1 protein inhibited HUVEC tube formation. TCGA database revealed significant correlation between  h HSS1 and  BRCA2  (r = −0.224,  P  < 0.0005),  ADAMTS1  (r = −0.132,  P  <0.01) and endostatin (r = 0.141,  P  < 0.005).    Conclusions   h HSS1-overexpression modulates signaling pathways involved in tumorigenesis.  h HSS1 inhibits glioma-induced cell cycle progression, cell migration, invasion and angiogenesis. Our data suggest that  h HSS1 is a potential therapeutic for malignant glioblastoma possessing significant antitumor and anti-angiogenic activity.

bmc cancer

Human hematopoietic signal peptide-containing secreted 1 (hHSS1) modulates genes and pathways in glioma: implications for the regulation of tumorigenicity and angiogenesis