Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1
Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1
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星形胶质细胞升高基因 1 通过抑制转录因子 FOXO1 促进乳腺癌增殖
DOI：
10.1038/onc.2009.171
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发表时间：
2009-09-10
期刊：
影响因子：
8
通讯作者：
Li, M.
中科院分区：
文献类型：
--
作者：
Li, J.;Yang, L.;Li, M.
我们以前报道过星形胶质细胞升高基因-1（AEG-1）在人乳腺癌中表达上调。然而，AEG-1在乳腺癌发生发展中的生物学功能仍有待阐明。在这项研究中，我们检测了AEG-1对细胞增殖的影响，发现AEG-1的上调与Ki 67的增加显著相关（P< 0.001）。AEG-1在MCF-7和MDA-MB-435乳腺癌细胞中的异位表达显著增强了细胞的增殖和非贴壁依赖性生长能力，而用shRNA沉默内源性AEG-1则抑制了细胞的增殖和软琼脂上的集落形成能力。此外，这些增殖效应与两种关键细胞周期抑制剂p27 Kip 1和p21 Cip 1的减少显著相关。此外，我们进一步证明AEG-1可以通过PI 3 K/Akt信号通路诱导FOXO 1的磷酸化来下调FOXO 1的转录活性。这些观察结果在临床人类原发性乳腺癌标本中得到进一步证实，其中AEG-1的高水平表达与FOXO 1的表达呈负相关。综上所述，我们的研究结果提供了一个新的机制，AEG-1诱导乳腺癌细胞增殖的第一个证明，我们的研究结果表明，AEG-1可能在乳腺癌的肿瘤发生中发挥重要作用。
We have previously reported that astrocyte elevated gene-1 (AEG-1) was upregulated in human breast cancer. However, the biological function of AEG-1 in the development and progression of breast cancer remains to be clarified. In this study, we examined the effect of AEG-1 on cell proliferation and found that AEG-1 upregulation was significantly linked to increased Ki67 (P< 0.001). Ectopic expression of AEG-1 in MCF-7 and MDA-MB-435 breast cancer cells dramatically enhanced cell proliferation and their ability of anchorage-independent growth, whereas silencing endogenous AEG-1 with shRNAs inhibited cell proliferation and colony-forming ability of the cells on soft agar. Furthermore, these proliferative effects were significantly associated with decreases of p27 Kip1 and p21 Cip1 two key cell-cycle inhibitors. Moreover, we further demonstrated that AEG-1 could downregulate the transcriptional activity of FOXO1 by inducing its phosphorylation through the PI3K/Akt signaling pathway. These observations were further confirmed in clinical human primary breast cancer specimens, in which high-level expression of AEG-1 was inversely correlated with the expression of FOXO1. Taken together, our results provide the first demonstration of a novel mechanism by which AEG-1 induces proliferation of breast cancer cell, and our findings suggest that AEG-1 might play an important role in tumorigenesis of breast cancer.