Acylglycerol kinase promotes cell proliferation and tumorigenicity in breast cancer via suppression of the FOXO1 transcription factor.
Acylglycerol kinase promotes cell proliferation and tumorigenicity in breast cancer via suppression of the FOXO1 transcription factor.
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酰基甘油激酶通过抑制 FOXO1 转录因子促进乳腺癌细胞增殖和致瘤性
DOI：
10.1186/1476-4598-13-106
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发表时间：
2014-05-08
期刊：
影响因子：
37.3
通讯作者：
Song L
中科院分区：
文献类型：
--
作者：
Wang X;Lin C;Zhao X;Liu A;Zhu J;Li X;Song L
研究背景酰基甘油激酶（Acylglycerol kinase，AGK）在多种肿瘤中过度表达。AGK在乳腺癌中的临床意义和生物学作用，然而，仍有待建立.MethodsAGK在乳腺癌细胞系，配对患者组织中的表达，采用免疫印迹和实时PCR测定。采用免疫组化方法检测203例乳腺癌组织中AGK的表达，探讨AGK表达与乳腺癌临床病理特征的关系。功能测定，如集落形成，锚定非依赖性生长和BrdU测定，以及异种移植肿瘤模型被用来确定AGK在人类乳腺癌进展中的致癌作用。AGK对FOXO 1反式活性的影响进行了进一步研究，使用荧光素酶报告分析，并通过检测FOXO 1的下游genes. ResultsIn，我们报告，AGK在乳腺癌细胞和临床组织中显着过表达。免疫组化分析显示AGK的表达与患者的临床病理特征，包括临床分期和肿瘤结节转移（TNM）分类显著相关。与AGK水平较低的患者相比，AGK表达水平较高的乳腺癌患者的总生存期较短。我们获得了有价值的见解AGK在乳腺癌细胞中的表达机制，通过证明过表达AGK显着增强，而沉默内源性AGK抑制，乳腺癌细胞的增殖和致瘤性在体外和体内。AGK过表达可促进乳腺癌细胞G1-S期的转变，其机制可能与激活AKT、抑制FOXO 1的反式活性、下调细胞周期蛋白依赖性激酶p21 Cip 1和p27 Kip 1以及上调细胞周期调节因子cyclin D1有关。这些发现提供了新的证据，AGK在促进人类乳腺癌的增殖和肿瘤发生中起重要作用，并可能作为一种新的预后生物标志物和治疗靶点。
BackgroundAcylglycerol kinase (AGK) is reported to be overexpressed in multiple cancers. The clinical significance and biological role of AGK in breast cancer, however, remain to be established.MethodsAGK expression in breast cancer cell lines, paired patient tissues were determined using immunoblotting and Real-time PCR. 203 human breast cancer tissue samples were analyzed by immunochemistry (IHC) to investigate the relationship between AGK expression and the clinicopathological features of breast cancer. Functional assays, such as colony formation, anchorage-independent growth and BrdU assay, and a xenograft tumor model were used to determine the oncogenic role of AGK in human breast cancer progression. The effect of AGK on FOXO1 transactivity was further investigated using the luciferase reporter assays, and by detection of the FOXO1 downstream genes.ResultsHerein, we report that AGK was markedly overexpressed in breast cancer cells and clinical tissues. Immunohistochemical analysis showed that the expression of AGK significantly correlated with patients’ clinicopathologic characteristics, including clinical stage and tumor-nodule-metastasis (TNM) classification. Breast cancer patients with higher levels of AGK expression had shorter overall survival compared to patients with lower AGK levels. We gained valuable insights into the mechanism of AGK expression in breast cancer cells by demonstrating that overexpressing AGK significantly enhanced, whereas silencing endogenous AGK inhibited, the proliferation and tumorigenicity of breast cancer cells bothin vitroandin vivo. Furthermore, overexpression of AGK enhanced G1-S phase transition in breast cancer cells, which was associated with activation of AKT, suppression of FOXO1 transactivity, downregulation of cyclin-dependent kinase inhibitorsp21Cip1andp27Kip1and upregulation of the cell cycle regulatorcyclin D1.ConclusionsTaken together, these findings provide new evidence that AGK plays an important role in promoting proliferation and tumorigenesis in human breast cancer and may serve as a novel prognostic biomarker and therapeutic target in this disease.
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DOI：
10.1158/1078-0432.ccr-09-2937
发表时间：
2010-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Li Y;Zhang T;Korkaya H;Liu S;Lee HF;Newman B;Yu Y;Clouthier SG;Schwartz SJ;Wicha MS;Sun D
通讯作者：
Sun D
一种产生溶血磷脂酸的新型酰基甘油激酶可调节前列腺癌细胞中与 EGFR 的串扰。
DOI：
10.1083/jcb.200407123
发表时间：
2005-06-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bektas M;Payne SG;Liu H;Goparaju S;Milstien S;Spiegel S
通讯作者：
Spiegel S
DOI：
10.1073/pnas.0406789102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Huang, H;Regan, KM;Tindall, DJ
通讯作者：
Tindall, DJ
影响因子：
64.8
作者：
Medema, RH;Kops, GJPL;Burgering, BMT
通讯作者：
Burgering, BMT
影响因子：
64.5
作者：
Paik, Ji-Hye;Kollipara, Ramya;DePinho, Ronald A.
通讯作者：
DePinho, Ronald A.