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

Abstract

BackgroundHuman Hematopoietic Signal peptide-containing Secreted 1 (hHSS1) is a truly novel protein, defining a new class of secreted factors. We have previously reported that ectopic overexpression of hHSS1 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 hHSS1 on glioma-derived cells and endothelial cells to elucidate the molecular mechanisms underlying the anti-tumorigenic effects of hHSS1.MethodsGene expression profiling of human glioma U87 and A172 cells overexpressing hHSS1 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 hHSS1 on HUVEC tube formation were determined by transwell and matrigel assays. Correlation was made between hHSS1 expression and specific genes in glioblastoma samples in the TCGA database.ResultsWe 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 hHSS1effects upon glioblastoma growth. U87-overexpressing hHSS1 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 hHSS1 significantly lost their ability to migrate (P < 0.001) and to invade (P < 0.01) through matrigel matrix. hHSS1-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 hHSS1 protein inhibited HUVEC tube formation. TCGA database revealed significant correlation between hHSS1 and BRCA2 (r = −0.224, P < 0.0005), ADAMTS1 (r = −0.132, P <0.01) and endostatin (r = 0.141, P < 0.005).ConclusionshHSS1-overexpression modulates signaling pathways involved in tumorigenesis. hHSS1 inhibits glioma-induced cell cycle progression, cell migration, invasion and angiogenesis. Our data suggest that hHSS1 is a potential therapeutic for malignant glioblastoma possessing significant antitumor and anti-angiogenic activity.

Squaring the EMC – how promoting membrane protein biogenesis impacts cellular functions and organismal homeostasis

“…EMC6 knockdown increases glioblastoma cell proliferation, whereas overexpression slows proliferation, inhibits invasiveness and enhances chemotherapeutic sensitivityall properties consistent with some role in tumour suppression (Shen et al, 2016). EMC10-2 overexpression also inhibits glioma-induced cell cycle progression and invasion (Junes-Gill et al, 2014). EMC6 overexpression improved survival in a glioma xenograft mouse model, attributed to induction of autophagy and PI3K-Akt-mTOR signalling pathway downregulation (Shen et al, 2016).…”

“…EMC10 pleiotropy was first hinted at by the discovery that hematopoietic stem cells express two splice variants. In constrast to full-length TMD-containing EMC10, EMC10-2 (also known as HSS1) lacks a discernible TMD and is secreted into the extracellular space (Junes-Gill et al, 2011;Junes-Gill et al, 2014). EMC10-2 is biologically active and mediates a range of cellline-dependent effects.…”

Recent advance in molecular angiogenesis in glioblastoma: the challenge and hope for anti-angiogenic therapy

“…Table 1 Recently discovered pro-and anti-angiogenesis factors Pro-angiogenesis TGLI1 [63], H19 [51], C/EBPbeta [14], MCSF [15], annexin A2 [39], CXCR4 [66], Oct-3/4 [16], miR-31 [50], miR-148a, HSP47 [38] Anti-angiogenesis hHSS1 [29], NNC55-0396 [30], TTAC-0001 [67], calpastatin [68], miR-137 [65], EZH2 [65], BMP7v [31], PDCD10 [32], JSI-124 [33] Brain Tumor Pathol…”

“…Unfortunately, targeted anti-angiogenic therapy with Avastin, a monoclonal antibody against vascular endothelial growth factor, could induce temporary remission of the cancer on MRI, but does not effectively prolong the overall survival time [28]. Overexpressing human hematopoietic signal peptidecontaining secreted 1 (hHSS1), a novel protein defined as a new class of secreted factors, could apparently inhibit tube formation in GBM and hence significantly decrease the GBM-induced cell cycle progression, migration, invasion and angiogenesis [29]. NNC55-0396, a T-type Ca 2?…”

EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay

“…18 In an in vitro study, EMC10 was suggested as a potential therapeutic target for malignant glioblastoma after being found to exert cell proliferation inhibition, invasion, angiogenesis in endothelial cells, and cell migration in glioma cell lines. 19,20 In schizophrenia mouse models, reduced Mirta22 (human EMC10 ortholog) levels completely rescued the dendritic deficits and spine formation at the hippocampal pyramidal neurons, thus suggesting a key role in neuronal dendrites and spine development. 21 Furthermore, studies revealed that knockout mouse (emc10 −/− ) showed effects on their behavior (hyperactivity, abnormal gait, and abnormal vocalization), decreased bone mineral content, persistence of hyaloid vascular system, cardiovascular issues (decreased heart rate), deceased corpuscular volume in females, thrombocytopenia, metabolic effects, and infertility phenotypes in males (MGI: 5548589).…”