miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6.
miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6.
复制标题
miR-211 通过靶向 Cyclin D1 和 CDK6 抑制上皮性卵巢癌增殖和细胞周期进展
DOI：
10.1186/s12943-015-0322-4
复制
发表时间：
2015-03-11
期刊：
影响因子：
37.3
通讯作者：
Lou G
中科院分区：
文献类型：
--
作者：
Xia B;Yang S;Liu T;Lou G
上皮性卵巢癌是卵巢癌发病率和死亡率的重要原因。MicroRNAs在癌症的发生和发展中发挥着重要作用。MicroRNA miR-211定位于Trpm1基因内含子6上的15q13-q14，该位点在肿瘤中经常丢失。它的功能和功能的丧失已经在正常和癌细胞和组织中得到了描述。已知miR-211在卵巢癌中表达异常：然而，其功能及其在卵巢癌中功能丧失的下游影响尚未被描述。方法我们分析了miR-211在卵巢癌原发组织和正常卵巢组织中的表达，以及在卵巢癌细胞系OVCAR3、Caov3、OVCA429、SKOV3和A2780中的表达。通过细胞计数、四甲基偶氮唑盐比色、集落形成、细胞周期、PI/Annexin V染色等方法研究miR-211对EoC细胞增殖和凋亡的影响。开发了一个荧光素酶报告系统来评估miR-211对预测靶标的调控。分析已发现的靶点在卵巢癌组织中的表达水平及其与miR-211表达的相关性。最后，将稳定表达miR-211的OVCAR3或对照细胞注射到小鼠皮下，检测miR-211对肿瘤的活体作用。结果与正常卵巢组织和人卵巢表面上皮细胞相比，卵巢上皮性肿瘤组织和卵巢细胞系中miR-211的表达分别下调。研究发现，MIR-211能将细胞阻滞在G0/G1期，抑制细胞增殖，诱导细胞凋亡。Cyclin D1和CDK6被发现是miR-211的直接靶点，当在表达miR-211的EOC细胞中过表达时，可以恢复细胞的增殖能力。结论miR-211是控制Cyclin D1和CDK6表达的肿瘤抑制因子，其下调导致Cyclin D1和CDK6的过度表达，从而增强EoC细胞的增殖能力。
BackgroundEpithelial ovarian cancer (EOC) is a significant cause of morbidity and mortality. MicroRNAs play important roles in cancer development and progression. The microRNA miR-211 is localized on intron 6 of theTrpm1gene at 15q13-q14, a locus that is frequently lost in neoplasms. Its function and loss-of-function have been described in normal and cancer cells and tissues. miR-211 is known to be dysregulated in ovarian cancer: however, its function and the downstream effect of its loss-of-function in ovarian cancer have not been described before.MethodsWe analyzed miR-211 expression in clinical samples of primary EOC tissues compared to normal epithelial ovarian tissues and in the EOC cell lines: OVCAR3, Caov3, OVCA429, SKOV3 and A2780 compared to human ovarian surface epithelial cells. We then investigated the effect of miR-211 on EOC cell proliferation and apoptosis by counting cell numbers, MTT, colony formation, cell cycle, and PI/Annexin V staining assays. A luciferase reporter system was developed to assess miR-211 regulation of the predicted targets. Expression level of discovered targets and correlation with miR-211 expression were analyzed in EOC tissues. Finally, OVCAR3 stably expressing miR-211 or control cells were injected subcutaneously into mice to determinein vivoeffect of miR-211 on tumorigenesis.ResultsWe found that the expression of miR-211 is downregulated in EOC tissues and cell lines compared to normal epithelial ovarian tissue and human ovarian surface epithelial cells, respectively. miR-211 was found to arrest cells in the G0/G1-phase, inhibit proliferation and induce apoptosis. Cyclin D1 and CDK6 were found to be direct targets of miR-211, and when overexpressed in miR-211-expressing EOC cells, could restore proliferative ability. Finally,in vitroinvestigation confirmed that miR-211 is a tumor suppressor that controls Cyclin D1 and CDK6 expression.ConclusionsOur results demonstrate that miR-211 is a tumor suppressor that controls expression of Cyclin D1 and CDK6, and that its downregulation results in overexpression of Cyclin D1 and CDK6 which increases proliferation ability of EOC cells to proliferate compared to normal cells.
登录
查看更多内容
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
影响因子：
6.5
作者：
Bell, Rachel E.;Khaled, Mehdi;Levy, Carmit
通讯作者：
Levy, Carmit
DOI：
10.1073/pnas.90.24.11513
发表时间：
1993-12-15
影响因子：
11.1
作者：
KATO, JY;SHERR, CJ
通讯作者：
SHERR, CJ
影响因子：
--
作者：
Feenstra, M;Veltkamp, M;Tilanus, M
通讯作者：
Tilanus, M