Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target.
Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target.
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DOI：
10.18632/oncotarget.3078
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发表时间：
2015-02-20
期刊：
影响因子：
--
通讯作者：
Raabe EH
中科院分区：
文献类型：
--
作者：
Weingart MF;Roth JJ;Hutt-Cabezas M;Busse TM;Kaur H;Price A;Maynard R;Rubens J;Taylor I;Mao XG;Xu J;Kuwahara Y;Allen SJ;Erdreich-Epstein A;Weissman BE;Orr BA;Eberhart CG;Biegel JA;Raabe EH
非典型畸胎样横纹肌样瘤（AT/RT）是所有小儿脑肿瘤中最致命的。除了SMARCB 1（BAF 47/INI 1/SNF 5）染色质重塑基因中的功能缺失突变外，AT/RT的其他分子驱动因素知之甚少。LIN 28 A和LIN 28 B是调节数千种RNA的干细胞因子，并在侵袭性癌症中表达。我们在AT/RT原发性肿瘤和细胞系中鉴定出高水平的LIN 28 A和LIN 28 B，而let-7家族的LIN 28调节的microRNA水平相应较低。在AT/RT细胞系CHLA-06-ATRT和BT37中通过慢病毒shRNA敲低LIN 28 A抑制生长、细胞增殖和集落形成并诱导凋亡。与空载体对照相比，原位异种移植模型中LIN 28 A的抑制导致中位生存期增加一倍以上（48天vs 115天）。LIN 28 A敲除导致let-7 b和let-7 g微小RNA的表达增加以及KRAS mRNA的下调。AT/RT原发性肿瘤表达增加的丝裂原活化蛋白（MAP）激酶途径活性，MEK抑制剂selumetinib（AZD 6244）降低AT/RT生长并增加细胞凋亡。这些数据表明LIN 28/RAS/MAP激酶是AT/RT肿瘤发生的关键驱动因素，并表明靶向该途径可能是这种侵袭性儿科恶性肿瘤的治疗选择。
Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. We identified high-levels of LIN28A and LIN28B in AT/RT primary tumors and cell lines, with corresponding low levels of the LIN28-regulated microRNAs of the let-7 family. Knockdown of LIN28A by lentiviral shRNA in the AT/RT cell lines CHLA-06-ATRT and BT37 inhibited growth, cell proliferation and colony formation and induced apoptosis. Suppression of LIN28A in orthotopic xenograft models led to a more than doubling of median survival compared to empty vector controls (48 vs 115 days). LIN28A knockdown led to increased expression of let-7b and let-7g microRNAs and a down-regulation of KRAS mRNA. AT/RT primary tumors expressed increased mitogen activated protein (MAP) kinase pathway activity, and the MEK inhibitor selumetinib (AZD6244) decreased AT/RT growth and increased apoptosis. These data implicate LIN28/RAS/MAP kinase as key drivers of AT/RT tumorigenesis and indicate that targeting this pathway may be a therapeutic option in this aggressive pediatric malignancy.
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DOI：
10.1158/1078-0432.ccr-10-3349
发表时间：
2011-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Raabe EH;Lim KS;Kim JM;Meeker A;Mao XG;Nikkhah G;Maciaczyk J;Kahlert U;Jain D;Bar E;Cohen KJ;Eberhart CG
通讯作者：
Eberhart CG
影响因子：
12.7
作者：
Korshunov A;Ryzhova M;Jones DT;Northcott PA;van Sluis P;Volckmann R;Koster J;Versteeg R;Cowdrey C;Perry A;Picard D;Rosenblum M;Giangaspero F;Aronica E;Schüller U;Hasselblatt M;Collins VP;von Deimling A;Lichter P;Huang A;Pfister SM;Kool M
通讯作者：
Kool M
影响因子：
7.5
作者：
Cao, Dengfeng;Liu, Aijun;Li, Jianping
通讯作者：
Li, Jianping
影响因子：
4.5
作者：
Hafner, Markus;Max, Klaas E. A.;Tuschl, Thomas
通讯作者：
Tuschl, Thomas
影响因子：
15.9
作者：
Lee, Ryan S.;Stewart, Chip;Roberts, Charles W. M.
通讯作者：
Roberts, Charles W. M.