The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells.
The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells.
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DOI：
10.18632/oncotarget.15991
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发表时间：
2017-05-09
期刊：
影响因子：
--
通讯作者：
Brodie C
中科院分区：
文献类型：
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作者：
Brodie S;Lee HK;Jiang W;Cazacu S;Xiang C;Poisson LM;Datta I;Kalkanis S;Ginsberg D;Brodie C
尽管胶质母细胞瘤（GBM）治疗的新治疗方法取得了进展，但12-14个月的中位生存期并未发生显著变化。因此，迫切需要确定在患者生存中发挥作用的分子机制。在这里，我们分析了一种新的lncRNA，TALNEC 2的表达和功能，它是使用E2 F1调节的lncRNA的RNA测序鉴定的。TALNEC 2定位于胞质溶胶，其表达受E2 F1调节和细胞周期依赖性。TALNEC 2在预后不良的GBM、来自短期存活者的GBM标本以及胶质瘤细胞和胶质瘤干细胞（GSC）中高度表达。在各种癌细胞系中，TALNEC 2的沉默抑制细胞增殖并将细胞阻滞在细胞周期的G1\S期。此外，TALNEC 2的沉默降低了GSC的自我更新和间充质转化，增加了这些细胞对辐射的敏感性，并延长了携带GSC衍生的异种移植物的小鼠的存活期。使用miRNA阵列分析，我们鉴定了在沉默细胞中改变的与细胞周期进展、增殖和间充质转化相关的特定miRNA。两种下调的miRNA，miR-21和miR-191，介导了TALNEC 2对GSC的干细胞性和间充质转化的一些作用。总之，我们鉴定了一种新的E2 F1调节的lncRNA，其在GBM和短期存活患者的肿瘤中高度表达。TALNEC 2的表达与GSC的致瘤潜力增加及其对辐射的抗性相关。我们得出结论，TALNEC 2是治疗GBM的有吸引力的治疗靶点。
Despite advances in novel therapeutic approaches for the treatment of glioblastoma (GBM), the median survival of 12-14 months has not changed significantly. Therefore, there is an imperative need to identify molecular mechanisms that play a role in patient survival. Here, we analyzed the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 was localized to the cytosol and its expression was E2F1-regulated and cell-cycle dependent. TALNEC2 was highly expressed in GBM with poor prognosis, in GBM specimens derived from short-term survivors and in glioma cells and glioma stem cells (GSCs). Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines. In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts. Using miRNA array analysis, we identified specific miRNAs that were altered in the silenced cells that were associated with cell-cycle progression, proliferation and mesenchymal transformation. Two of the downregulated miRNAs, miR-21 and miR-191, mediated some of TALNEC2 effects on the stemness and mesenchymal transformation of GSCs. In conclusion, we identified a novel E2F1-regulated lncRNA that is highly expressed in GBM and in tumors from patients of short-term survival. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs and their resistance to radiation. We conclude that TALNEC2 is an attractive therapeutic target for the treatment of GBM.