AEG-1 Is a Target of Perifosine and Is Over-Expressed in Gastric Dysplasia and Cancers
AEG-1 Is a Target of Perifosine and Is Over-Expressed in Gastric Dysplasia and Cancers
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AEG-1 是哌立福辛的靶标，在胃发育不良和癌症中过度表达
DOI：
10.1007/s10620-013-2735-5
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发表时间：
2013-10-01
影响因子：
3.1
通讯作者：
Wang, Xuerong
中科院分区：
文献类型：
--
作者：
Huang, Wenbin;Yang, Li;Wang, Xuerong
背景哌立福辛是一种烷基磷脂，是Akt抑制剂，可抑制多种癌细胞的生长。目的：探讨哌立福新对胃癌细胞生长的抑制作用及其调控机制。方法：将AEG-1特异性siRNA瞬时转染胃癌细胞，用磺酰罗丹明B法检测细胞活力。采用qRT-PCR和western blot分析检测细胞信号分子的mRNA表达和蛋白水平。结果哌立福新沿着抑制Akt/GSK 3 β/C-MYC信号通路，降低AEG-1基因表达。siRNA抑制AEG-1表达后，cyclin D1在mRNA和蛋白水平的表达均显著下调，并抑制胃癌细胞的生长。AEG-1在异型增生和胃癌组织中的表达明显高于正常胃粘膜（P< 0.01）。结论哌立福新可能通过抑制Akt/GSK 3 β/C-MYC信号通路介导的AEG-1的表达，进而抑制cyclin D1的表达，从而抑制胃癌细胞的生长。AEG-1可能在胃癌的发生、发展过程中起重要作用，可作为哌立福新的治疗靶点。
BackgroundPerifosine, an alkylphospholipid, is an Akt inhibitor which inhibits the growth of diverse cancer cells. We have reported its inhibitory effects on the growth of gastric cancer cells recently, but its molecular mechanisms are still largely unknown.AimsThe purpose of this study was to investigate the effect and regulatory mechanism of perifosine in gastric cancer.MethodsCell viability was determined by sulforhodamine B assay after transiently transfected with AEG-1 specific siRNAs. qRT-PCR and western blot assay were used to determine the mRNA expression and proteins levels of cell signaling molecules examined. Immunohistochemistry was used to detect the AEG-1 expression in 87 gastric carcinomas, 60 dysplasia, and 47 normal gastric mucosa.ResultsPerifosine decreased AEG-1 gene expression along with inhibition of Akt/GSK3β/C-MYC signaling pathway. Knockdown of AEG-1 using siRNA led to significant down-regulation of cyclin D1 expression at both mRNA level and protein level, and inhibited the growth of gastric cancer cells. AEG-1 expression was elevated in gastric dysplasia and cancer tissues compared to normal gastric mucosa (P< 0.01). AEG-1 over-expression correlated with diffuse type of gastric cancer and advanced tumor stages.ConclusionsPerifosine inhibits the growth of gastric cancer cells possibly through inhibition of the Akt/GSK3β/C-MYC signaling pathway—mediated down-regulation of AEG-1 that subsequently down-regulated cyclin D1. AEG-1 may play an important role in the carcinogenesis and progression of gastric cancer and could be a therapeutic target of perifosine.