The novel long non-coding RNA TALNEC2 regulates the stemness and mesenchymal transformation of glioma stem cells and their exosome mediated interaction with microglia cells
Brodie S, Cazacu S, Poisson L, Kalkanis S, Ginsburg D, and Brodie C. The novel long non-coding RNA TALNEC2 regulates the stemness and mesenchymal transformation of glioma stem cells and their exosome mediated interaction with microglia cells. J Extracell Vesicles 2017; 6:7.
J Extracell Vesicles
Glioblastoma (GBM) are characterised by an infiltrative nature and high resistance to radio- and chemotherapy. GBM contain a subpopulation of glioma stem cells (GSCs) that is implicated in therapy resistance and tumour recurrence. Long non-coding RNAs (lncRNAs) play major roles in various processes associated with tumorigenesis and stemness. Here, we report the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 expression was increased in astrocytic tumours in a grade-dependent manner and in mesenchymal GBM compared with the proneural and G-CIMP subtypes. Moreover, TLANEC2 was more significantly expressed in GBM specimens derived from short-term (<9 months) compared to long-term (>3 years) survivors. TALNEC2 was not expressed in normal brain tissues, astrocytes or neural stem cells, but its expression was high in GSCs and glioma cell lines. Silencing of TALNEC2 resulted in a decrease in the self-renewal of GSCs, expression of stemness and mesenchymal markers and in increased sensitivity of GSCs to radiation (3 Gy). Moreover, silencing of TALNEC2 resulted in inhibition of xenograft growth and prolonged animal survival. UsingmiRNA sequencing we identified specific miRNAs that were altered in the silenced cells and that mediated TALNEC2 effects via targeting of NF-kB, SOX2 and Dicer pathways. TALNEC2 was highly enriched in exosomes secreted from GSCs and played a role in the interaction of GSCs withmicroglia and in their polarisation by altering the delivery of miR-21 and miR-195 to these cells. Moreover, TALNEC2 was detected in serum exosomes of mice bearing GSCderived xenografts. In conclusion, we identified a novel E2F1-regulated lncRNA that induced mesenchymal transformation and stemness of GSCs. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs, their resistance to radiation and with the cross talk of GSCs and microglia. We conclude that TALNEC2 is an attractive therapeutic target for the targeting of GSCs and the treatment of GBM.