Next, coculture experiments indicated that HCC cell-derived exosomes promoted the cell growth, migration and invasion of HCC cells and had the ability to shuttle miRNAs to recipient cells. Further, our data showed that Vps4A, a key regulator of exosomes biogenesis, was frequently down-regulated in HCC tissues. The reduction of Vps4A in HCC tissues was associated with tumor progression and metastasis. In vitro studies revealed that Vps4A repressed the growth, colony formation, migration and invasion of HCC cells. We further investigated the role and involvement of Vps4A in suppressing the bioactivity of
exosomes and characterized its ability to weaken the cell response to exosomes. By small RNA sequencing, we demonstrated that Vps4A facilitated the secretion of oncogenic miRNAs in Z-VAD-FMK solubility dmso exosomes, as well as accumulation and uptake of
tumor suppressor miRNAs in cells. A subset of Vps4A-associated miRNAs was identified. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the phosphatidylinositol-3-kinase (PI3K) /Akt signaling pathway was the most likely candidate pathway for modulation by these miRNAs. Indeed, we proved that the PI3K/Akt pathway was inactivated by Vps4A-overexpression. Conclusion: Exosome-mediated miRNA transfer is an important mechanism of self-modulation of the miRNA expression profiles in HCC cells. Vps4A may function as a tumor suppressor, which utilizes exosomes as mediators to regulate the secretion and uptake of miRNAs in hepatoma cells. These observations provide new insights into the development of HCC. This GPCR Compound Library article is protected by copyright. All rights reserved. “
“Death receptors, a subset of the tumor necrosis factor (TNF) receptor (TNFR) superfamily that includes TNFR1, CD95 (Fas, Apo-1),
and the TRAIL (TNF-related apoptosis-inducing ligand) receptors, transduce signals capable of engaging apoptosis or necrosis,1 depending on the status of signaling molecules in the cells. Ligation of one such receptor, cluster of differentiation 95 (CD95), has catastrophic consequences in vivo, because this results in lethal, fulminant liver destruction.2 In this issue 上海皓元 of HEPATOLOGY, Hikita et al.3 employ a conditional gene deletion model to explore the molecular mechanisms of this liver failure. CD95, cluster of differentiation 95; FADD, Fas-associated protein with death domain; TNF, tumor necrosis factor; XIAP, X-linked inhibitor of apoptosis protein. Upon ligation, CD95 rapidly recruits an intracellular adapter molecule, Fas-associated protein with death domain (FADD), which in turn binds to and activates the initiator caspase, caspase-8.1 The activation of caspase-8 requires two steps: dimerization of the inactive “pro-form” of the molecule, followed by autocleavage, which generates a stable, active protease.