Translational research : the journal of laboratory and clinical medicine
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The 7 members of the A3 family of cytidine deaminases (A3A to A3H) share a conserved catalytic activity that converts cytidines in single-stranded (ss) DNA into uridines, thereby inducing mutations. After their initial identification as cell-intrinsic defenses against HIV and other retroviruses, A3s were also found to impair many additional viruses. Moreover, some of the A3 proteins (A3A, A3B, and A3H haplotype I) are dysregulated in cancer cells, thereby causing chromosomal mutations that can be selected to fuel progression of malignancy. ⋯ Two independent lines of evidence supported the conclusion that the multiprotein CRLpVHL complex is necessary for A3 degradation. CRLpVHL more effectively induced degradation of nuclear, procancer A3 (A3B) than the cytoplasmic, antiretroviral A3 (A3G). These results identify specific cellular factors that regulate A3s post-translationally.
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Neuroblastoma (NB) is the most common extracranial pediatric solid cancer originating from undifferentiated neural crest cells. NB cells express EZH2 and GLI1 genes that are known to maintain the undifferentiated phenotype of cancer stem cells (CSC) in NB. Recent studies suggest that tumor-derived extracellular vesicles (EVs) can regulate the transformation of surrounding cells into CSC by transferring tumor-specific molecules they contain. ⋯ Using these models, we observed an enrichment of GLI1 and EZH2 mRNAs in NB-derived EVs. As a consequence of the uptake of NB-derived EVs, the host cells increased the expression levels of GLI1 and EZH2. These results suggest the alteration of the expression profile of stromal cells through an EV-based mechanism, and point the GLI1 and EZH2 mRNAs in the EV cargo as diagnostic biomarkers in NB.