Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells.
Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells.
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DOI：
10.18632/oncotarget.346
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发表时间：
2011-11
期刊：
影响因子：
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通讯作者：
Riggins GJ
中科院分区：
文献类型：
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作者：
Weber GL;Parat MO;Binder ZA;Gallia GL;Riggins GJ
多形性胶质母细胞瘤（GBM）是一种高度侵袭性和致死性的脑肿瘤。肿瘤细胞的侵袭使得完全的手术切除是不可能的，并且降低了其他治疗方法的疗效。突变、拷贝数变化和表达模式的全基因组分析为GBM中常见的遗传异常提供了新的见解。我们分析了已发表的数据，并确定了GBM中最常改变的侵袭和运动途径。其中最显著的是黏附和整合素信号通路，以及细胞外基质相互作用途径。我们绘制了这些通路的变化图谱，发现它们包括IA类PI3K的催化PIK3CA和调控PIK3R1亚基基因。通过慢病毒介导的shRNA表达在GBM细胞系中单独敲除这些基因中的任何一个，在所有测试的细胞系中，增殖、迁移和侵袭都减少。敲低PIK3CA或PIK3R1均可降低FAK活性，敲低PIK3R1可降低MMP2水平。我们得出结论，PIK3R1，像PIK3CA一样，是GBM的潜在治疗靶点，它也影响肿瘤细胞的生长和运动。
Glioblastoma multiforme (GBM) is a highly invasive and deadly brain tumor. Tumor cell invasion makes complete surgical resection impossible and reduces the efficacy of other therapies. Genome-wide analyses of mutations, copy-number changes, and expression patterns have provided new insights into genetic abnormalities common in GBM. We analyzed published data and identified the invasion and motility pathways most frequently altered in GBM. These were most notably the focal adhesion and integrin signaling, and extracellular matrix interactions pathways. We mapped alterations in each of these pathways and found that they included the catalytic PIK3CA and regulatory PIK3R1 subunit genes of the class IA PI3K. Knockdown of either of these genes separately in GBM cell lines by lentiviral-mediated shRNA expression resulted in decreased proliferation, migration, and invasion in all lines tested. FAK activity was reduced by knockdown of either PIK3CA or PIK3R1, and MMP2 levels were reduced by knockdown of PIK3R1. We conclude that PIK3R1, like PIK3CA, is a potential therapeutic target in GBM and that it also influences tumor cell growth and motility.