The HSulf-1 gene encodes an extracellular 6-O-endosulfatase and regulates the sulfation status of heparan sulfate proteoglycans (HSPG). We have demonstrated that promoter hypermethylation is correlated with the HSulf-1 silencing in gastric cancer. To investigate the functional importance of HSulf-1 silencing in gastric cancer, we restored HSulf-1 expression in the gastric cancer cell line MKN28, which lacks endogenous HSulf-1. Following restoration of expression, HSulf-1 inhibited cell proliferation, motility, and invasion in vitro, as well as significantly suppressing the MKN28 xenograft model (P < 0.05). No noticeable changes in proliferation and motility were observed following restoration of HSulf-1 in another gastric cancer cell line, namely AGS cells. Interestingly, in MKN28 cells, which have been reported to be dependent on extracellular Wnt signaling, we found that HSulf-1 inhibited the transcriptional activity of the Wnt ⁄ b-catenin pathway and downregulated its targeted genes. Conversely, in AGS cells, in the constitutive Wnt ⁄ b-catenin pathway is active, HSulf-1 had no effect on the activity of the Wnt ⁄ b-catenin pathway. Furthermore, transfection of Wnt3a cDNA or b-catenin shRNA resulted in rescue or enhancement, respectively, of the effects of HSulf-1 in MKN28 cells. Furthermore, HSPG epitope analysis confirmed that HSulf-1 affected the structure of heparan sulfate on the cell surface. Together, the results of the present study suggest that extracellular HSulf-1 may function as a negative regulator of proliferation and invasion in gastric cancer by suppressing Wnt ⁄ b-catenin signaling at the cell surface. (Cancer Sci 2011; 102: 1815-1821 G astric cancer is the second most common cause of cancerrelated deaths worldwide.(1,2) Understanding the mechanisms involved in gastric tumorigenesis and metastasis is important for the development of new effective therapeutic agents.The HSulf-1 gene, characterized as Human ortholog of Qsulf-1, can hydrolyze the sulfate ester bonds of heparan sulfate proteoglycans (HSPG), leading to removal of the sulfate at the 6-O position of glucosamine. (3,4) It is believed that changes in the sulfation status of HSPG can affect their interactions with signaling molecules and therefore modulate signal transduction. (3,(5)(6)(7)(8)
Extracellular vesicles (EVs) are a heterogeneous group of membranous structures, which can be secreted by most cell types. As a product of paracrine secretion, EVs are considered to be a regulatory mediator for intercellular communication. There are many bioactive cargos in EVs, such as proteins, lipids, and nucleic acids. As the precursor cell of vascular endothelial cells (ECs), endothelial progenitor cells (EPCs) are first discovered in peripheral blood. With the development of studies about the functions of EPCs, an increasing number of researchers focus on EPC‐derived EVs (EPC‐EVs). EPC‐EVs exert key functions for promoting angiogenesis in regenerative medicine and show significant therapeutic effects on a variety of diseases such as circulatory diseases, kidney diseases, diabetes, bone diseases, and tissue/organ damages. This article reviews the current knowledge on the role of EPC‐EVs in regenerative medicine and disease treatment, discussing the main challenges and future directions in this field.
Ebola virus (EBOV) causes a highly lethal hemorrhagic fever syndrome in humans and has been associated with mortality rates of up to 91% in Zaire, the most lethal strain. Though the viral envelope glycoprotein (GP) mediates widespread inflammation and cellular damage, these changes have mainly focused on alterations at the protein level, the role of microRNAs (miRNAs) in the molecular pathogenesis underlying this lethal disease is not fully understood. Here, we report that the miRNAs hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p were induced in human umbilical vein endothelial cells (HUVECs) following expression of EBOV GP. Among the proteins encoded by predicted targets of these miRNAs, the adhesion-related molecules tissue factor pathway inhibitor (TFPI), dystroglycan1 (DAG1) and the caspase 8 and FADD-like apoptosis regulator (CFLAR) were significantly downregulated in EBOV GP-expressing HUVECs. Moreover, inhibition of hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p, or overexpression of TFPI, DAG1 and CFLAR rescued the cell viability that was induced by EBOV GP. Our results provide a novel molecular basis for EBOV pathogenesis and may contribute to the development of strategies to protect against future EBOV pandemics. Ebola virus, glycoprotein, microRNAs, cytotoxicity Citation:Sheng MM, Zhong Y, Chen Y, Du JC, Ju XW, Zhao C, Zhang GG, Zhang LF, Liu KT, Yang N, Xie P, Li DS, Zhang MQ, Jiang CY. Hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p inhibitors can reduce the cytotoxicity of Ebola virus glycoprotein in vitro. Sci China Life Sci, 2014, 57: 959 -972,
BackgroundEMX2 is a human orthologue of the Drosophila empty spiracles homeobox gene that has been implicated in embryogenesis. Recent studies suggest possible involvement of EMX2 in human cancers; however, the role of EMX2 in carcinogenesis needs further exploration.ResultsIn this study, we reported that down-regulation of EMX2 expression was significantly correlated with EMX2 promoter hypermethylation in gastric cancer. Restoring EMX2 expression using an adenovirus delivery system in gastric cancer cell lines lacking endogenous EMX2 expression led to inhibition of cell proliferation and Wnt signaling pathway both in vitro and in a gastric cancer xenograft model in vivo. In addition, we observed that animals treated with the adenoviral EMX2 expression vector had significantly better survival than those treated with empty adenoviral vector.ConclusionOur study suggests that EMX2 is a putative tumor suppressor in human gastric cancer. The adenoviral-EMX2 may have potential as a novel gene therapy for the treatment of patients with gastric cancer.
Background Human periodontal ligament stem cells (hPDLSCs) are ideal seed cells for periodontal regeneration. A greater understanding of the dynamic protein profiles during osteogenic differentiation contributed to the improvement of periodontal regeneration tissue engineering. Methods Tandem Mass Tag quantitative proteomics was utilized to reveal the temporal protein expression pattern during osteogenic differentiation of hPDLSCs on days 0, 3, 7 and 14. Differentially expressed proteins (DEPs) were clustered and functional annotated by Gene Ontology (GO) terms. Pathway enrichment analysis was performed based on the Kyoto Encyclopedia of Genes and Genomes database, followed by the predicted activation using Ingenuity Pathway Analysis software. Interaction networks of redox-sensitive signalling pathways and oxidative phosphorylation (OXPHOS) were conducted and the hub protein SOD2 was validated with western blotting. Results A total of 1024 DEPs were identified and clustered in 5 distinctive clusters representing dynamic tendencies. The GO enrichment results indicated that proteins with different tendencies show different functions. Pathway enrichment analysis found that OXPHOS was significantly involved, which further predicted continuous activation. Redox-sensitive signalling pathways with dynamic activation status showed associations with OXPHOS to various degrees, especially the sirtuin signalling pathway. SOD2, an important component of the sirtuin pathway, displays a persistent increase during osteogenesis. Data are available via ProteomeXchange with identifier PXD020908. Conclusion This is the first in-depth dynamic proteomic analysis of osteogenic differentiation of hPDLSCs. It demonstrated a dynamic regulatory mechanism of hPDLSC osteogenesis and might provide a new perspective for research on periodontal regeneration. Graphical abstract
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