The transcriptional network for mesenchymal transformation of brain tumours.
The transcriptional network for mesenchymal transformation of brain tumours.
复制标题
作者：
调控细胞向生理或病理状态转变的转录网络的推断仍然是系统生物学的核心挑战。间充质表型是人类恶性胶质瘤肿瘤侵袭性的标志，但负责实施相关分子特征的调控程序在很大程度上是未知的。在这里，我们展示了对胶质瘤特异性调控网络的逆向工程和无偏见的询问，揭示了激活恶性胶质瘤中间充质基因表达的转录模块。两个转录因子（C/EBPβ和Stat3）作为间质转化的协同启动者和主要调节剂出现。C/EBPβ和Stat3的异位共表达沿异常间充质谱系重编程神经干细胞，而在胶质瘤细胞中消除这两个因子会导致间充质特征的崩溃并降低肿瘤的侵袭性。在人类胶质瘤中，C/EBPβ和Stat3的表达与间充质分化相关，并预示着不良的临床预后。这些结果表明，激活一个小的调控模块是启动和维持癌细胞异常表型状态的必要和充分条件。
Inference of transcriptional networks that regulate transitions into physiologic or pathologic cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumor aggressiveness in human malignant glioma but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here, we show that reverse-engineering and unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPβ and Stat3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and Stat3 reprograms neural stem cells along the aberrant mesenchymal lineage whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumor aggressiveness. In human glioma, expression of C/EBPβ and Stat3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results reveal that activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.
登录
查看更多内容
影响因子：
56.9
作者：
Bonni, A;Sun, Y;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
50.3
作者：
Bachoo, RM;Maher, EA;DePinho, RA
通讯作者：
DePinho, RA
影响因子：
14.8
作者：
Margolin, Adam A.;Wang, Kai;Califano, Andrea
通讯作者：
Califano, Andrea
影响因子：
30.8
作者：
Bussemaker, HJ;Li, H;Siggia, ED
通讯作者：
Siggia, ED