Co-amplification of phosphoinositide 3-kinase enhancer A and cyclin-dependent kinase 4 triggers glioblastoma progression.
Co-amplification of phosphoinositide 3-kinase enhancer A and cyclin-dependent kinase 4 triggers glioblastoma progression.
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磷酸肌醇 3 激酶增强子 A 和细胞周期蛋白依赖性激酶 4 的共同扩增触发胶质母细胞瘤进展
作者：
Qi Q;Kang SS;Zhang S;Pham C;Fu H;Brat DJ;Ye K
胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，预后差。染色体12 q13-q15的扩增（细胞周期蛋白依赖性激酶4（CDK 4）扩增子）经常在包括GBM在内的许多人类癌症中观察到。磷酸肌醇3-激酶增强子（Phosphoinositide 3-kinase enhancer，PIKE）是一组GTP结合蛋白，属于centaurin GT3家族的一个亚类，由位于CDK 4扩增子上的CENTG 1编码。然而，CDK 4扩增子在GBM形成中的病理学意义仍不完全清楚。在目前的研究中，我们表明，在TP 53/PTEN双敲除GBM小鼠模型中，PIKE-A和CDK 4的共表达与单独过表达这些基因相比，可额外缩短胶质瘤发病和存活的潜伏期。因此，p-mTOR、p-Akt和p-ERK途径在脑肿瘤中高度上调，与它们在GBM细胞系中稳定转染的CDK 4和PIKE-A的致癌活性一致。因此，我们的研究结果支持PIKE扩增或过表达与CDK 4协同作用以驱动GBM肿瘤发生。
Glioblastoma (GBM) is the most common primary brain tumor and has a dismal prognosis. Amplification of chromosome 12q13-q15 (Cyclin-dependent kinase 4 (CDK4) amplicon) is frequently observed in numerous human cancers including GBM. Phosphoinositide 3-kinase enhancer (PIKE) is a group of GTP-binding proteins that belong to the subgroup of centaurin GTPase family, encoded by CENTG1 located in CDK4 amplicon. However, the pathological significance of CDK4 amplicon in GBM formation remains incompletely understood. In the current study, we show that co-expression of PIKE-A and CDK4 in TP53/PTEN double knockout GBM mouse model additively shortens the latency of glioma onset and survival compared to overexpression of these genes alone. Consequently, p-mTOR, p-Akt and p-ERK pathways are highly upregulated in the brain tumors, in alignment with their oncogenic activities by CDK4 and PIKE-A stably transfected in GBM cell lines. Hence, our findings support that PIKE amplification or overexpression coordinately acts with CDK4 to drive GBM tumorigenesis.
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