Expression of the miR-302/367 cluster in glioblastoma cells suppresses tumorigenic gene expression patterns and abolishes transformation related phenotypes.
Expression of the miR-302/367 cluster in glioblastoma cells suppresses tumorigenic gene expression patterns and abolishes transformation related phenotypes.
复制标题
DOI：
10.1002/ijc.29606
复制
发表时间：
2015-11-15
影响因子：
6.4
通讯作者：
Groner B
中科院分区：
文献类型：
--
作者：
Yang CM;Chiba T;Brill B;Delis N;von Manstein V;Vafaizadeh V;Oellerich T;Groner B
细胞转化由癌基因的激活和表观遗传景观的密切相关的发育重编程启动。转录因子、染色质状态调节因子和microRNA影响发育中的细胞命运，并稳定正常、分化细胞和癌细胞的表型。miR-302/367簇主要在人胚胎干细胞（hES）中表达，可以促进人和小鼠细胞的细胞重编程，并有助于iPSC的产生。我们已经利用miR-302/367簇的表观遗传重编程潜力来“去编程”肿瘤细胞，即将其基因表达模式转变为与更良性的细胞表型相关的替代程序。在广泛突变的U87 MG胶质母细胞瘤细胞中诱导miR-302/367簇显著抑制了转化相关蛋白的表达，例如，重编程因子OCT 3/4、SOX 2、KLF 4和c-MYC，以及维持胶质母细胞瘤干细胞样肿瘤增殖细胞所需的转录因子POU 3F 2、SALL 2和OLIG 2。它还减少了PI 3 K/AKT和STAT 3信号传导，阻碍了软琼脂中的集落形成和细胞迁移，并抑制了促炎细胞因子分泌。同时，miR-302/367簇恢复了神经元分化标志物的表达。最值得注意的是，表达miR-302/367簇的细胞失去了在裸鼠中形成肿瘤和建立肝转移的能力。在U87 MG胶质母细胞瘤细胞中诱导miR-302/367簇抑制多个转化相关基因的表达，消除这些细胞的肿瘤和转移形成潜力，并可能成为癌症治疗的新方法。 有什么新消息吗？ 正常细胞向恶性细胞的转化与体细胞向多能细胞的重编程有许多相似之处，这提高了重编程因子可用于对抗细胞转化的可能性。这项研究表明，通过表达miR-302/367簇，可以在高度异常的胶质母细胞瘤细胞中实现转化逆转和细胞特性正常化。miR-302/367显著改变基因表达模式，并以协调的方式消除转化相关表型。miR-302/367可预防肿瘤和转移形成，并恢复神经元分化的特征。这种肿瘤细胞的“去编程”可能成为癌症治疗的新概念。
Cellular transformation is initiated by the activation of oncogenes and a closely associated developmental reprogramming of the epigenetic landscape. Transcription factors, regulators of chromatin states and microRNAs influence cell fates in development and stabilize the phenotypes of normal, differentiated cells and of cancer cells. The miR‐302/367 cluster, predominantly expressed in human embryonic stem cells (hESs), can promote the cellular reprogramming of human and mouse cells and contribute to the generation of iPSC. We have used the epigenetic reprogramming potential of the miR‐302/367 cluster to “de‐program” tumor cells, that is, hift their gene expression pattern towards an alternative program associated with more benign cellular phenotypes. Induction of the miR‐302/367 cluster in extensively mutated U87MG glioblastoma cells drastically suppressed the expression of transformation related proteins, for example, the reprogramming factors OCT3/4, SOX2, KLF4 and c‐MYC, and the transcription factors POU3F2, SALL2 and OLIG2, required for the maintenance of glioblastoma stem‐like tumor propagating cells. It also diminished PI3K/AKT and STAT3 signaling, impeded colony formation in soft agar and cell migration and suppressed pro‐inflammatory cytokine secretion. At the same time, the miR‐302/367 cluster restored the expression of neuronal markers of differentiation. Most notably, miR‐302/367 cluster expressing cells lose their ability to form tumors and to establish liver metastasis in nude mice. The induction of the miR‐302/367 cluster in U87MG glioblastoma cells suppresses the expression of multiple transformation related genes, abolishes the tumor and metastasis formation potential of these cells and can potentially become a new approach for cancer therapy. What's new? The transformation of normal cells into malignant cells shares many similarities with the reprogramming of somatic cells into pluripotent cells, raising the possibility that reprogramming factors may be used to counteract cellular transformation. This study demonstrates that reversion of transformation and normalization of cellular properties can be achieved in highly‐aberrant glioblastoma cells through the expression of the miR‐302/367 cluster. miR‐302/367 drastically changes the gene expression pattern and abolishes transformation‐related phenotypes in a coordinated fashion. miR‐302/367 prevents tumor and metastasis formation and restores features of neuronal differentiation. Such “deprogramming” of tumor cells could potentially become a new concept for cancer therapy.