Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner.
Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner.
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DOI：
10.1002/stem.1322
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发表时间：
2013-05
期刊：
影响因子：
5.2
通讯作者：
Nakano, Ichiro
中科院分区：
文献类型：
--
作者：
Gu, Chunyu;Banasavadi-Siddegowda, Yeshavanth K.;Joshi, Kaushal;Nakamura, Yuko;Kurt, Habibe;Gupta, Snehalata;Nakano, Ichiro
关键词：
越来越多的证据表明，胶质瘤干细胞（GSCs）可能有助于高级别胶质瘤（HGG）的治疗耐药。虽然最近的研究表明丝氨酸/苏氨酸激酶MELK在多种癌症中大量表达，但MELK的功能和机制尚不清楚。在这里，我们证明了shRNA消耗MELK可以减少体内gsc来源的小鼠颅内肿瘤的生长，诱导GFAP（+）胶质细胞分化，从而降低肿瘤的恶性程度，延长荷瘤小鼠的生存期。91例HGG肿瘤的组织微阵列分析表明，MELK（+）细胞的比例是术后生存期的一个具有统计学意义的指标。从机制上讲，MELK受JNK信号的调节，并在gsc中与癌蛋白c-JUN形成复合物，但在正常祖细胞中不形成复合物。MELK沉默诱导p53表达，而p53抑制诱导MELK表达，表明MELK和p53表达是互斥的。此外，MELK沉默介导的GSC凋亡可以通过p53的药物抑制和p53基因沉默来部分挽救，这表明MELK在GSC中的作用依赖于p53。此外，GSCs辐照可显著提高MELK mRNA和蛋白在体内和体外的表达。在临床上，放疗和化疗失败后复发的HGG肿瘤与未治疗的新诊断的HGG肿瘤相比，MELK蛋白升高具有统计学意义。总之，我们的数据表明，GSCs，而不是正常细胞，依赖jnk驱动的MELK/c-JUN信号来调节其生存，维持GSCs处于未成熟状态，并以p53依赖的方式促进肿瘤放射耐药。
Accumulated evidence suggests that glioma stem cells (GSCs) may contribute to therapy resistance in high grade glioma (HGG). Although recent studies have shown that the serine/threonine kinase MELK is abundantly expressed in various cancers, the function and mechanism of MELK remain elusive. Here, we demonstrate that MELK depletion by shRNA diminishes the growth of GSC-derived mouse intracranial tumors in vivo, induces GFAP (+) glial differentiation of GSCs leading to decreased malignancy of the resulting tumors, and prolongs survival periods of tumor-bearing mice. Tissue microarray analysis with 91 HGG tumors demonstrates that the proportion of MELK (+) cells is a statistically significant indicator of post-surgical survival periods. Mechanistically, MELK is regulated by the JNK signaling and forms a complex with the oncoprotein c-JUN in GSCs but not in normal progenitors. MELK silencing induces p53 expression, whereas p53 inhibition induces MELK expression, indicating that MELK and p53 expression are mutually exclusive. Additionally, MELK silencing-mediated GSC apoptosis is partially rescued by both pharmacological p53 inhibition and p53 gene silencing, indicating that MELK action in GSCs is p53 dependent. Furthermore, irradiation of GSCs markedly elevates MELK mRNA and protein expression both in vitro and in vivo. Clinically, recurrent HGG tumors following the failure of radiation and chemotherapy exhibit a statistically significant elevation of MELK protein compared with untreated newly-diagnosed HGG tumors. Together, our data indicate that GSCs, but not normal cells, depend on JNK-driven MELK/c-JUN signaling to regulate their survival, maintain GSCs in an immature state, and facilitate tumor radioresistance in a p53-dependent manner.
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DOI：
10.1073/pnas.1007462107
发表时间：
2010-07-13
影响因子：
11.1
作者：
Baldwin, Amy;Grueneberg, Dorre A.;Munger, Karl
通讯作者：
Munger, Karl
影响因子：
11.2
作者：
Daginakatte, Girish C.;Gianino, Scott M.;Gutmann, David H.
通讯作者：
Gutmann, David H.
影响因子：
4
作者：
Le Page, Yann;Chartrain, Isabelle;Tassan, Jean-Pierre
通讯作者：
Tassan, Jean-Pierre
影响因子：
23.9
作者：
Lathia JD;Gallagher J;Heddleston JM;Wang J;Eyler CE;Macswords J;Wu Q;Vasanji A;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN
癌基因诱导的DNA损伤反应与衰老和癌症异染色质之间的相互作用。
影响因子：
21.3
作者：
Di Micco R;Sulli G;Dobreva M;Liontos M;Botrugno OA;Gargiulo G;dal Zuffo R;Matti V;d'Ario G;Montani E;Mercurio C;Hahn WC;Gorgoulis V;Minucci S;d'Adda di Fagagna F
通讯作者：
d'Adda di Fagagna F