Recent studies have reported the emerging role of microRNAs (miRNAs) in human cancers. We systematically characterized miRNA expression and editing in the human brain, which displays the highest number of A-to-I RNA editing sites among human tissues, and in de novo glioblastoma brain cancer. We identified 299 miRNAs altered in their expression and 24 miRNAs differently edited in human brain compared to glioblastoma tissues. We focused on the editing site within the miR-589–3p seed. MiR-589–3p is a unique miRNA almost fully edited (∼100%) in normal brain and with a consistent editing decrease in glioblastoma. The edited version of miR-589–3p inhibits glioblastoma cell proliferation, migration and invasion, while the unedited version boosts cell proliferation and motility/invasion, thus being a potential cancer-promoting factor. We demonstrated that the editing of this miRNA is mediated by ADAR2, and retargets miR-589–3p from the tumor-suppressor PCDH9 to ADAM12, which codes for the metalloproteinase 12 promoting glioblastoma invasion. Overall, our study dissects the role of a unique brain-specific editing site within miR-589–3p, with important anticancer features, and highlights the importance of RNA editing as an essential player not only for diversifying the genomic message but also for correcting not-tolerable/critical genomic coding sites.

Purpose: The Epstein-Barr virus (EBV) is present in the malignant Hodgkin/Reed-Sternberg (HRS) cells of 20% to 40% cases of Hodgkin lymphoma (HL) in Western countries. We were interested in the detection and quantification of cell-free plasma EBV-DNA as an indicator of biological and clinical characteristics in EBV-associated HL.Experimental Design: EBV was detected in peripheral blood compartments (whole blood, plasma, and mononuclear cells) at diagnosis by real-time PCR for the EBNA (EB nuclear antigen) region (n ¼ 93) and in HRS cells by in situ hybridization for EBV-encoded small RNAs (EBER; n ¼ 63). These data were correlated to histological and clinical characteristics, EBV serology, circulating cell-free DNA, and interleukin (IL)-6 levels.Results: Detection of EBV-DNA in plasma had a high specificity (90%), but a relatively low sensitivity (65%) to predict for EBV association. The viral load was higher in patients with advanced stage disease, older age in the presence of B-symptoms, and international prognostic score more than 2. The presence of EBV in HRS cells and higher plasma EBV-DNA copy numbers correlated to an increased frequency of tumor-infiltrating CD68þ macrophages in lymph node biopsies. Plasma EBV-DNA load correlated to circulating cell-free DNA and IL-6 levels, and inversely correlated to lymphocyte counts and EBNA1 antibody titers.Conclusion: Although the presence of EBV-DNA in peripheral blood cannot be regarded as a surrogate marker for EBER, the plasma EBV-DNA load at HL diagnosis is an indicator of disease activity and biological characteristics associated with negative prognosis. Moreover, the inverse correlation to EBNA1 antibody titers and lymphocyte counts may indicate a reduction in immunosurveillance, favoring the expansion of EBV-HRS cells in HL. Clin Cancer Res; 17(9); 2885-92. Ó2011 AACR.

the whole E13,5 brain and in the olfactory bulbs (OB) of E18,5 brain (Fig. 1b, Extended Data Fig. 1d, e). Also, neural stem cells (NSCs) isolated from Ambra1 cKO mice show increased levels of several cell-cycle regulatory proteins (Fig. 1c, Extended Data Fig. 1f, g), together with higher clonogenic potential and replication rate (Fig 1d, Extended Data Fig. 1h). Strikingly, levels of cyclin D1 and D2 proteins and phosphorylated pRb (S807/811) are highly increased both ex and in vivo (Fig. 1c, e, Extended Data Fig. 1g, i-m), suggesting an AMBRA1dependent Cyclin D modulation. Indeed, consistent with our previous results 7 , we find in neural ex vivo and in vitro cell lines that AMBRA1 directly binds and regulates the stability of N-Myc, via the phosphatase PP2A, thereby controlling Cyclin D1 and D2 transcription (Extended Data Fig. 1n-r). Moreover, we noticed that both cyclin D1 and D2 are highly resilient to proteasomal degradation in Ambra1-deficiency conditions (Fig. 1f, Extended Data Fig. 2a, b). In line with the fact that both Myc and D-type cyclins positively regulate G1/S transition 10,11 , Ambra1 cKO NSCs show a shorter G1 phase with faster entry into, and longer residence in S phase (Extended Data Fig. 2c). By reducing cyclin D/CDK kinase activity we could restore proliferation to wt levels (Extended Data Fig. 2d), highlighting the importance of accelerated G1/S transition in the AMBRA1depleted driven phenotype. Additionally, we found that due to Ambra1 deficiency, deregulated cell cycle progression is followed by increased cell death, a phenotype rescued upon cyclin D/CDK activity inhibition (Extended Data Fig. 2e, f). Of note, Ambra1 deficiency in neurodevelopment promotes staminal niche