While the importance of protein N‐glycosylation in cancer cell migration is well appreciated, the precise mechanisms by which N‐acetylglucosaminyltransferase V (GnT‐V) regulates cancer processes remain largely unknown. In the current study, we report that GnT‐V‐mediated N‐glycosylation of CD147/basigin, a tumor‐associated glycoprotein that carries β1,6‐N‐acetylglucosamine (β1,6‐GlcNAc) glycans, is upregulated during TGF‐β1‐induced epithelial‐to‐mesenchymal transition (EMT), which correlates with tumor metastasis in patients with hepatocellular carcinoma (HCC). Interruption of β1,6‐GlcNAc glycan modification of CD147/basigin decreased matrix metalloproteinase (MMP) expression in HCC cell lines and affected the interaction of CD147/basigin with integrin β1. These results reveal that β1,6‐branched glycans modulate the biological function of CD147/basigin in HCC metastasis. Moreover, we showed that the PI3K/Akt pathway regulates GnT‐V expression and that inhibition of GnT‐V‐mediated N‐glycosylation suppressed PI3K signaling. In summary, β1,6‐branched N‐glycosylation affects the biological function of CD147/basigin and these findings provide a novel approach for the development of therapeutic strategies targeting metastasis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
miR-362 is a recently discovered member of the microRNA family, and it modulates a variety of physical activities and plays an important role in the occurrence and development of many tumors. However, the biological functions of hsa-miR-362-5p in non-small-cell lung carcinoma (NSCLC) are unknown. Transwell assay and colony formation were used to determine the migration, invasion, and proliferation of NSCLC cells in vitro. A subcutaneous tumor model in nude mice was established to detect NSCLC tumor growth in vivo. The direct binding of miR-362 to the 3′UTR of Semaphorin 3A (Sema3A) was confirmed by luciferase reporter assay. In this study, we found that the level of miR-362 was higher in NSCLC tissues than in adjacent normal tissues and that the level of miR-362 expression was also elevated in five NSCLC cell lines (A549, 95-D, H1299, H292, and H460) relative to a human normal lung epithelial cell line (BEAS2B). Furthermore, miR-362 promoted NSCLC cell invasion, migration, and colony formation in vitro and tumor formation in vivo. Next, we identified the miR-362 target gene Sema3A, which is significantly correlated with metastasis. Sema3A expression was increased in normal tissues relative to NSCLC tissues. This result is consistent with the fact that miR-362 expression is negatively correlated with Sema3A expression in clinical tissue samples and indicated that miR-362 can regulate Sema3A expression in NSCLC cells and consequently affect NSCLC invasion, migration, and colony formation. Taken together, these findings on the newly identified miR-362/Sema3A axis elucidate the molecular mechanism of NSCLC invasion and migration and could lead to a potential therapeutic target in NSCLC treatment.
Activated hepatic stellate cells (HSCs) release pro-inflammatory and pro-fibrogenic factors. CXC chemokine-ligand-1 (CXCL1) is expressed on HSCs. We previously found that the CD147 is overexpressed in activated HSCs. In this study, we showed an important role of CD147 in promoting liver fibrosis by activating HSCs and upregulating expression of chemokines. Specifically, we found that CD147 specific deletion in HSCs mice alleviated CCl4-induced liver fibrosis and inhibited HSCs activation. Overexpression of CD147 upregulated the secretion of CXCL1. Meanwhile, CXCL1 promoted HSCs activation through autocrine. Treating with PI3K/AKT inhibitor could effectively suppress CD147-induced CXCL1 expression. Taken together, these findings suggest that CD147 regulates CXCL1 release in HSCs by PI3K/AKT signaling. Inhibition of CD147 attenuates CCl4-induced liver fibrosis and inflammation. Therefore, administration of targeting CD147 could be a promising therapeutic strategy in liver fibrosis.
Proteins are like miracle machines, playing important roles in living organisms. They perform vital biofunctions by further combining together and/or with other biomacromolecules to form assemblies or condensates such as membraneless organelles. Therefore, studying the self-assembly of biomacromolecules is of fundamental importance. In addition to their biological activities, protein assemblies also exhibit extra properties that enable them to achieve applications beyond their original functions. Herein, this study showed that in the presence of monosaccharides, ethylene glycols, and amino acids, β-lactoglobulin (β-LG) can form assemblies with specific structures, which were highly reproducible. The mechanism of the assembly process was studied through multi-scale observations and theoretical analysis, and it was found that the assembling all started from the formation of solute-rich liquid droplets via liquid–liquid phase separation (LLPS). These droplets then combined together to form condensates with elaborate structures, and the condensates finally evolved to form assemblies with various morphologies. Such a mechanism of the assembly is valuable for studying the assembly processes that frequently occur in living organisms. Detailed studies concerning the properties and applications of the obtained β-LG assemblies showed that the assemblies exhibited significantly better performances than the protein itself in terms of autofluorescence, antioxidant activity, and metal ion absorption, which indicates broad applications of these assemblies in bioimaging, biodetection, biodiagnosis, health maintenance, and pollution treatment. This study revealed that biomacromolecules, especially proteins, can be assembled via LLPS, and some unexpected application potentials could be found beyond their original biological functions.
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