MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1.
MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1.
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DOI：
10.18632/oncotarget.928
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Brodie C
中科院分区：
文献类型：
--
作者：
Bier A;Giladi N;Kronfeld N;Lee HK;Cazacu S;Finniss S;Xiang C;Poisson L;deCarvalho AC;Slavin S;Jacoby E;Yalon M;Toren A;Mikkelsen T;Brodie C
胶质母细胞瘤（GBM）是最常见和最具侵袭性的恶性星形细胞肿瘤，含有一小部分癌症干细胞（GSC）亚群，这些细胞与治疗耐药性和肿瘤复发有关。在这里，我们研究了miR-137（一种假定的抑制性miRNA）在GBM和GSC中的表达和功能。我们发现，与正常脑和神经干细胞（NSCs）相比，GBM和GSC中miR-137的表达显著降低，并且miR-137启动子在GBM标本中高甲基化。miR-137在分化的NSCs和GSCs中的表达增加，并且miR-137的过表达促进两种细胞类型的神经分化。此外，pre-miR-137显著降低了GSC和干细胞标志物Oct 4、Nanog、Sox 2和Shh的自我更新。我们发现RTVP-1是miR-137在GSC中的新靶点;用miR-137转染细胞降低了RTVP-1的表达和RTVP-1 3 '-UTR报告质粒的荧光素酶活性。此外，过表达缺少其3 '-UTR的RTVP-1质粒消除了miR-137对GSC自我更新的抑制作用。RTVP-1的沉默降低了GSC的自我更新，CXCR 4的表达和CXCR 4的过表达消除了RTVP-1沉默对GSC自我更新的抑制作用。这些结果表明，miR-137在GBM中下调，可能是由于启动子超甲基化。miR-137通过靶向下调CXCR 4的RTVP-1抑制GSC自我更新并促进其分化。因此，miR-137和RTVP-1是根除GSC和治疗GBM的有吸引力的治疗靶标。
Glioblastomas (GBM), the most common and aggressive malignant astrocytic tumors, contain a small subpopulation of cancer stem cells (GSCs) that are implicated in therapeutic resistance and tumor recurrence. Here, we study the expression and function of miR-137, a putative suppressor miRNA, in GBM and GSCs. We found that the expression of miR-137 was significantly lower in GBM and GSCs compared to normal brains and neural stem cells (NSCs) and that the miR-137 promoter was hypermethylated in the GBM specimens. The expression of miR-137 was increased in differentiated NSCs and GSCs and overexpression of miR-137 promoted the neural differentiation of both cell types. Moreover, pre-miR-137 significantly decreased the self-renewal of GSCs and the stem cell markers Oct4, Nanog, Sox2 and Shh. We identified RTVP-1 as a novel target of miR-137 in GSCs; transfection of the cells with miR-137 decreased the expression of RTVP-1 and the luciferase activity of RTVP-1 3'-UTR reporter plasmid. Furthermore, overexpression of RTVP-1 plasmid lacking its 3'-UTR abrogated the inhibitory effect of miR-137 on the self-renewal of GSCs. Silencing of RTVP-1 decreased the self-renewal of GSCs and the expression of CXCR4 and overexpression of CXCR4 abrogated the inhibitory effect of RTVP-1 silencing on GSC self-renewal. These results demonstrate that miR-137 is downregulated in GBM probably due to promoter hypermethylation. miR-137 inhibits GSC self-renewal and promotes their differentiation by targeting RTVP-1 which downregulates CXCR4. Thus, miR-137 and RTVP-1 are attractive therapeutic targets for the eradication of GSCs and for the treatment of GBM.
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影响因子：
9.2
作者：
Deng Y;Deng H;Bi F;Liu J;Bemis LT;Norris D;Wang XJ;Zhang Q
通讯作者：
Zhang Q
影响因子：
6.2
作者：
Langevin, Scott M.;Stone, Roslyn A.;Bunker, Clareann H.;Lyons-Weiler, Maureen A.;LaFramboise, William A.;Kelly, Lori;Seethala, Raja R.;Grandis, Jennifer R.;Sobol, Robert W.;Taioli, Emanuela
通讯作者：
Taioli, Emanuela
影响因子：
12.4
作者：
Fareh, M.;Turchi, L.;Virolle, T.
通讯作者：
Virolle, T.
影响因子：
8.4
作者：
Chen, Lingchao;Wang, Xiaofeng;Jiang, Chuanlu
通讯作者：
Jiang, Chuanlu
影响因子：
11.5
作者：
O'Brien, Catherine Adell;Kreso, Antonija;Jamieson, Catriona H. M.
通讯作者：
Jamieson, Catriona H. M.