Knockdown of FLOT1 Impairs Cell Proliferation and Tumorigenicity in Breast Cancer through Upregulation of FOXO3a
Knockdown of FLOT1 Impairs Cell Proliferation and Tumorigenicity in Breast Cancer through Upregulation of FOXO3a
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FLOT1 的敲低通过 FOXO3a 的上调损害乳腺癌中的细胞增殖和致瘤性
DOI：
10.1158/1078-0432.ccr-10-3068
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发表时间：
2011-05-15
影响因子：
11.5
通讯作者：
Song, Libing
中科院分区：
文献类型：
--
作者：
Lin, Chuyong;Wu, Zhiqiang;Song, Libing
目的：脂筏是细胞膜上的特殊结构域，是各种分子协调各种信号转导过程的物理平台。脂筏标记物flotinlin -1 （FLOT1）参与了癌症的发展，但其确切机制尚不清楚。本研究的目的是探讨FLOT1在乳腺癌细胞发生中的作用及其在疾病进展中的临床意义。实验设计：采用免疫组化（IHC）方法分析212例石蜡包埋的乳腺癌临床标本中FLOT1的表达。在体外和体内研究了FLOT1对细胞增殖和肿瘤发生的影响。通过Western blotting和荧光素酶报告基因分析，确定下调FLOT1对细胞周期调控因子表达和FOXO3a转录活性的影响。结果：IHC分析显示，在212例石蜡包埋的乳腺癌标本中，有129例（60.8%）高表达FLOT1。FLOT1的总体表达水平与乳腺癌的临床分期及不良患者生存率显著相关。引人注目的是，我们发现，在体外和体内，沉默FLOT1均能抑制乳腺癌细胞的增殖和致瘤性，这进一步被证明与抑制Akt活性、增强FOXO3a转录活性、上调周期蛋白依赖性激酶抑制剂p21Cip1和p27Kip1以及下调CDK调节因子cyclin D1的机制相关。结论：FLOT1在促进人乳腺癌的增殖和肿瘤发生中发挥重要作用，可能是一种新的预后生物标志物和治疗靶点。临床癌症研究；17 (10);3089 - 99。AACR©2011。
Purpose: Lipid rafts, specialized domains in cell membranes, function as physical platforms for various molecules to coordinate a variety of signal transduction processes. Flotinllin-1 (FLOT1), a marker of lipid rafts, is involved in the progression of cancer, but the precise mechanism remains unclear. The aim of the present study was to examine the role of FLOT1 on the tumorigenesis of breast cancer cells and its clinical significance in progression of the disease. Experimental Design: FLOT1 expression was analyzed in 212 paraffin-embedded, archived clinical breast cancer samples by using immunohistochemistry (IHC). The effect of FLOT1 on cell proliferation and tumorigenesis was examined in vitro and in vivo. Western blotting and luciferase reporter analyses were carried out to identify the effects of downregulating FLOT1 on expression of cell cycle regulators and transcriptional activity of FOXO3a. Results: IHC analysis revealed high expression of FLOT1 in 129 of the 212 (60.8%) paraffin-embedded archived breast cancer specimens. The overall expression level of FLOT1 significantly correlated with clinical staging and poor patient survival of breast cancer. Strikingly, we found that silencing FLOT1 inhibited proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo, which was further shown to be mechanistically associated with suppression of Akt activity, enhanced transcriptional activity of FOXO3a, upregulation of cyclin-dependent kinase inhibitor p21Cip1 and p27Kip1, and downregulation of the CDK regulator cyclin D1. Conclusions: FLOT1 plays an important role in promoting proliferation and tumorigenesis of human breast cancer and may represent a novel prognostic biomarker and therapeutic target for the disease. Clin Cancer Res; 17(10); 3089–99. ©2011 AACR.