Postgraduate School of National Core Research Center for Nanomedical Technology, Seoul, Korea.
Neuro Oncol. 2013 Mar;15(3):290-304. doi: 10.1093/neuonc/nos387. Epub 2013 Jan 16.
Ongoing characterization of glioma has revealed that Akt signaling plays a crucial role in gliomagenesis. In mouse models, however, Akt alone was not sufficient to induce glioma.
We established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1(G12V) (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis.
Transgene expressions were spatiotemporally restricted without any developmental abnormality of embryos and persisted at cerebellum and medulla in adult zebrafish. DAAkt1 alone induced glioma (with visible bumps at the head), with incidences of 36.6% and 49% at 6 and 9 months, respectively. Histologically, gliomas showed various histologic grades, increased proliferation, and frequent invasion into the fourth ventricle. Preferential location of small tumors at periventricular area and coexpression of Her4 suggested that tumors originated from Ptf1a- and Her4-positive progenitor cells at ventricular zone. Gliomagenesis was principally mediated by activation of survival pathway through upregulation of survivin genes. Although DARac1 alone was incapable of gliomagenesis, when coexpressed with DAAkt1, gliomagenesis was accelerated, showing higher tumor incidences (62.0% and 73.3% at 6 and 9 months, respectively), advanced histologic grade, invasiveness, and shortened survival. DARac1 upregulated survivin2, cyclin D1, β-catenin, and snail1a but downregulated E-cadherin, indicating that DARac1 promotes gliomagenesis by enhancing proliferation, survival, and epithelial-to-mesenchymal transition. On pharmacologic tests, only Akt1/2 inhibitor effectively suppressed gliomagenesis, inhibited cellular proliferation, and induced apoptosis in established gliomas.
The zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.
不断深入的胶质瘤研究揭示 Akt 信号通路在胶质瘤发生中起着至关重要的作用。然而，在小鼠模型中，仅 Akt 的过表达不足以诱导胶质瘤的发生。
我们构建了在 ptf1a 结构域过表达显性激活型（DA）人 Akt1 或 Rac1(G12V)（DARac1）的转基因斑马鱼，并研究了导致胶质瘤发生的转基因表型和机制。
转基因表达具有时空限制，胚胎没有任何发育异常，在成年斑马鱼的小脑和延髓中持续存在。单独的 DAAkt1 诱导了胶质瘤（头部出现可见的肿块），6 个月和 9 个月的发生率分别为 36.6%和 49%。组织学上，胶质瘤显示出不同的组织学分级，增殖增加，并且经常侵犯第四脑室。小肿瘤优先位于脑室周围区域，以及 Her4 的共表达表明肿瘤起源于脑室区的 Ptf1a 和 Her4 阳性祖细胞。胶质瘤的发生主要是通过生存途径的激活来介导的，这是通过上调 survivin 基因实现的。虽然 DARac1 单独不能诱导胶质瘤的发生，但与 DAAkt1 共表达时，可加速胶质瘤的发生，表现为更高的肿瘤发生率（6 个月和 9 个月时分别为 62.0%和 73.3%）、更高级别的组织学分级、侵袭性和更短的生存时间。DARac1 上调 survivin2、cyclin D1、β-catenin 和 snail1a，但下调 E-cadherin，表明 DARac1 通过增强增殖、生存和上皮-间质转化来促进胶质瘤的发生。在药物试验中，只有 Akt1/2 抑制剂能有效抑制胶质瘤的发生，抑制细胞增殖，并诱导已建立的胶质瘤细胞凋亡。
斑马鱼模型强化了 Akt 信号通路在胶质瘤发生中的关键作用，并提示 Rac1 是参与进展的重要蛋白。
