ERRα的抑制通过直接靶向纤连蛋白来抑制三阴性乳腺癌细胞的上皮-间质转化。
Inhibition of ERRα suppresses epithelial mesenchymal transition of triple negative breast cancer cells by directly targeting fibronectin.
作者信息
Wu Ying-Min, Chen Zhuo-Jia, Liu Hao, Wei Wei-Dong, Lu Lin-Lin, Yang Xiang-Ling, Liang Wei-Ting, Liu Tao, Liu Huan-Liang, Du Jun, Wang Hong-Sheng
机构信息
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
出版信息
Oncotarget. 2015 Sep 22;6(28):25588-601. doi: 10.18632/oncotarget.4436.
Triple-negative breast cancer (TNBC) patients have poor prognosis due to the aggressive metastatic behaviors. Our study reveals that expression of estrogen related receptor α (ERRα) is significantly (p < 0.01) positively associated with high grade tumors and lymph node metastasis, while negatively correlated with overall survival (OS), in 138 TNBC patients. Targeted inhibition of ERRα by its inverse agonist XCT-790 or si-RNA obviously inhibits in vitro motility of TNBC cells. While over expression of ERRα triggers the invasion and migration of TNBC cells. Further, si-ERRα and XCT-790 inhibit the epithelial mesenchymal transition (EMT) of TNBC cells with increasing the expression of E-cadherin and decreasing fibronectin (FN) and vimentin. While XCT-790 has no effect on the expression of EMT related transcription factors such as Snail or Slug. Further, inhibitors of MAPK, PI3K/Akt, NF-κB signal molecules, which are activated by XCT-790, can not attenuate the suppression effects of XCT-790 on EMT. Alternatively, luciferase reporter gene assays and ChIP analysis indicate that ERRα can directly bind with FN promoter at ERR response element-3 (ERRE-1), ERRE-3, and ERRE-4, while XCT-790 reduces this bond. In vivo data show that ERRα expression is significantly (p < 0.05) correlated with FN in clinical TNBC patients. In MDA-MB-231 tumor xenograft models, XCT-790 decreases the expression of FN, inhibits the growth and lung metastasis, and suppresses the EMT. Our results demonstrate that ERRα functions as a metastasis stimulator and its targeted inhibition may be a new therapeutic strategy for TNBC treatment.
三阴性乳腺癌(TNBC)患者由于具有侵袭性转移行为,预后较差。我们的研究表明,在138例TNBC患者中,雌激素相关受体α(ERRα)的表达与高级别肿瘤和淋巴结转移显著正相关(p < 0.01),而与总生存期(OS)负相关。其反向激动剂XCT-790或小干扰RNA(si-RNA)对ERRα的靶向抑制明显抑制了TNBC细胞的体外运动能力。而ERRα的过表达则引发TNBC细胞的侵袭和迁移。此外,si-ERRα和XCT-790通过增加E-钙黏蛋白的表达并降低纤连蛋白(FN)和波形蛋白的表达,抑制TNBC细胞的上皮-间质转化(EMT)。而XCT-790对EMT相关转录因子如Snail或Slug的表达没有影响。此外,被XCT-790激活的丝裂原活化蛋白激酶(MAPK)、磷脂酰肌醇-3激酶/蛋白激酶B(PI3K/Akt)、核因子κB(NF-κB)信号分子的抑制剂,不能减弱XCT-790对EMT的抑制作用。另外,荧光素酶报告基因检测和染色质免疫沉淀分析表明,ERRα可在ERR反应元件-3(ERRE-1)、ERRE-3和ERRE-4处直接与FN启动子结合,而XCT-790可减少这种结合。体内数据显示,在临床TNBC患者中,ERRα表达与FN显著相关(p < 0.05)。在MDA-MB-231肿瘤异种移植模型中,XCT-790降低了FN的表达,抑制了肿瘤生长和肺转移,并抑制了EMT。我们的结果表明,ERRα起着转移刺激因子的作用,对其进行靶向抑制可能是TNBC治疗的一种新的治疗策略。