ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling
ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling
复制标题
DOI：
10.1530/ec-18-0364
复制
发表时间：
2018-12-01
影响因子：
2.9
通讯作者：
Miyamoto, Hiroshi
中科院分区：
文献类型：
--
作者：
Inoue, Satoshi;Mizushima, Taichi;Miyamoto, Hiroshi
我们研究了ATF 2在尿路上皮癌生长中的功能作用，ATF 2是一种转录因子，通常通过磷酸化ERK/MAPK信号激活。在肿瘤性和非肿瘤性尿路上皮细胞中，雄激素受体（AR）的表达水平与磷酸化ATF 2的表达水平相关。AR阳性膀胱癌细胞中的双氢睾酮处理还诱导磷酸化ATF 2和磷酸化ERK的表达以及ATF 2的核转位和转录活性。同时，ATF 2基因的shRNA敲除可显著降低AR阳性膀胱癌细胞的存活率、迁移率和侵袭力，并使细胞凋亡率、G 0/G1期和S/G2/M期分别显著增加和减少，但对AR阴性膀胱癌细胞无影响。此外，与对照肿瘤相比，在异种移植荷瘤小鼠中表达ATF 2-shRNA的AR阳性肿瘤的生长被延迟。在稳定表达AR的永生化人正常尿路上皮SVHUC细胞中，ATF 2敲除还导致对由化学致癌物3-甲基胆蒽诱导的肿瘤转化的显著抑制，以及Bcl-2/细胞周期蛋白-A2/细胞周期蛋白-D1/JUN/MMP-2的表达，而不是AR阴性SVHUC细胞。最后，手术标本的免疫组织化学显示，与非肿瘤性尿路上皮组织相比，膀胱肿瘤中ATF 2/磷酸化ATF 2/磷酸化ERK表达显着升高。多变量分析进一步显示，中/强ATF 2表达和磷酸化ATF 2阳性分别是低级别肿瘤复发（风险比（HR）=2.956，P=0.045）和肌肉浸润性肿瘤癌症特异性死亡率（HR= 5.317，P=0.012）的独立预测因子。因此，ATF 2似乎通过AR途径在尿路上皮细胞中被激活，并促进尿路上皮癌的发展和进展。
We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR)=2.956, P=0.045) and cancer-specific mortality of muscle-invasive tumors (HR= 5.317, P=0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.