曲古菌素A抑制乳腺肿瘤干细胞的自我更新  

Tricostantin A inhibits self-renewal of breast cancer stem cells in vitro

作　　者：彭黎[1] 李福喜[1] 邵文凤[1] 熊静波[1] 

机构地区：[1]南方医科大学基础医学院细胞生物学教研室,广东广州510515

出　　处：《南方医科大学学报》2013年第10期1421-1426,共6页Journal of Southern Medical University

基　　金：国家自然科学基金(81071810;81172058)~~

摘　　要：目的研究组蛋白乙酰化酶抑制剂曲古菌素A对乳腺肿瘤干细胞自我更新的影响;初步研究其抑制乳腺肿瘤干细胞自我更新的机制。方法悬浮培养乳腺癌细胞系MDA-MB-468、MDA-MB-231、MCF-7和SKBR3,用不同浓度曲古菌素A处理悬浮培养乳腺癌细胞7 d,用0.1%DMSO作对照;用次级细胞球形成率和乳腺癌细胞初级细胞球细胞中肿瘤干细胞即CD44+/CD24-细胞群的百分比评价曲古菌素A对乳腺癌干细胞自我更新的影响;乳腺癌细胞初级细胞球细胞中CD44+/CD24-细胞群的百分比用流式细胞仪检测,凋亡细胞百分比用Annexin-V法在流式细胞仪检测,Nanog、Sox2和Oct4 mRNA的表达用定量PCR法检测。结果 100 nmol/L和500 nmol/L曲古菌素A均能部分抑制4个乳腺癌细胞系中肿瘤干细胞的自我更新,但10 nmol/L不行;500 nmol/L曲古菌素A诱导乳腺癌细胞初级细胞球细胞凋亡;曲古菌素A能下调乳腺癌细胞初级细胞球细胞Nanog和Sox2mRNA的表达。结论曲古菌素A能部分抑制乳腺癌干细胞的自我更新,其机制与其能下调乳腺癌初级细胞球细胞Nanog和Sox2表达相关联,提示临床可用低浓度组蛋白乙酰化酶抑制剂和其他抗癌药物联用以便获得较好的乳腺肿瘤干细胞自我更新抑制效果,胚胎干细胞核心转录因子Nanog和Sox2可能作为肿瘤治疗的新靶标。Objective To investigate the effect of tricostantm A （TSA） on self-renewal of breast cancer stem cells and explore the mechanisms. Methods Breast cancer cell lines MDA-MB-468, MDA-MB-231, MCF-7 and SKBR3 were cultured in suspension and treated with different concentrations of TSA for 7 days, using 0.1% DMSO as the control. Secondary mammosphere formation efficiency and percentage of CD44＋/CD24- sub-population in the primary mammospheres were used to evaluate the effects of TSA on self-renewal of breast cancer stem cells. The breast cancer stem cell surface marker CD44 ＋/CD24- and the percentage of apoptosis in the primary mammospheres were assayed using flow cytometry. The mRNA expressions of Nanog, Sox2 and Oct4 in the primary mammospheres were assayed with quantitative PCR. Results TSA at both 100 and 500 nmol/L, but not at 10 nmol/L, partially inhibited the self-renewal of breast cancer stem cells from the 4 cell lines. TSA at 500 nmol/L induced cell apoptosis in the primary mammospheres. TSA down-regulated the mRNA expression of Nanog and Sox2 in the primary mammospheres. Conclusions TSA can partially inhibit the self-renewal of breast cancer stem cells through a mechanism involving the down-regulation of Nanog and Sox2 expression, indicating the value of combined treatments with low-dose TSA and other anficancer drugs to achieve maximum inhibition of breast cancer stem cell self-renewaL The core transcriptional factor of embryonic stem cells Nanog and Sox2 can be potential targets of anticancer therapy.

关 键 词：肿瘤干细胞 乳腺癌 组蛋白乙酰化酶抑制 NANOG 

分 类 号：R737.9[医药卫生—肿瘤]