Wang Kefeng, Sun Yin, Tao Wei, Fei Xiang, Chang Chawnshang
Department of Urology, Shengjing Hospital, China Medical University, Shenyang, 110004, China; George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14642, USA.
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Cancer Lett. 2017 May 28;394:1-12. doi: 10.1016/j.canlet.2016.12.036. Epub 2017 Jan 13.
Increasing evidence has demonstrated that the androgen receptor (AR) plays important roles to promote the metastasis of clear cell renal cell carcinoma (ccRCC). The detailed mechanisms, especially how AR functions via altering the circular RNAs (circRNAs) remain unclear. Here we identified a new circRNA (named as circHIAT1) whose expression was lower in ccRCCs than adjacent normal tissues. Targeting AR could suppress ccRCC cell progression via increasing circHIAT1 expression. ChIP assay and luciferase assay demonstrated that AR suppressed circHIAT1 expression via regulating its host gene, Hippocampus Abundant Transcript 1 (HIAT1) expression at the transcriptional level. The consequences of AR-suppressed circHIAT1 resulted in deregulating miR-195-5p/29a-3p/29c-3p expressions, which increased CDC42 expression to enhance ccRCC cell migration and invasion. Increasing this newly identified signal via circHIAT1 suppressed AR-enhanced ccRCC cell migration and invasion. Together, these results suggested that circHIAT1 functioned as a metastatic inhibitor to suppress AR-enhanced ccRCC cell migration and invasion. Targeting this newly identified AR-circHIAT1-mediated miR-195-5p/29a-3p/29c-3p/CDC42 signals may help us develop potential new therapies to better suppress ccRCC metastasis.
越来越多的证据表明，雄激素受体（AR）在促进透明细胞肾细胞癌（ccRCC）转移中发挥重要作用。其详细机制，尤其是AR如何通过改变环状RNA（circRNA）发挥作用仍不清楚。在此，我们鉴定出一种新的circRNA（命名为circHIAT1），其在ccRCC中的表达低于相邻正常组织。靶向AR可通过增加circHIAT1表达来抑制ccRCC细胞进展。染色质免疫沉淀（ChIP）实验和荧光素酶实验表明，AR通过在转录水平调节其宿主基因海马丰富转录本1（HIAT1）的表达来抑制circHIAT1表达。AR抑制circHIAT1的结果导致miR-195-5p/29a-3p/29c-3p表达失调，从而增加细胞分裂周期蛋白42（CDC42）的表达，以增强ccRCC细胞的迁移和侵袭。通过circHIAT1增强这一新发现的信号可抑制AR增强的ccRCC细胞迁移和侵袭。总之，这些结果表明circHIAT1作为一种转移抑制因子，可抑制AR增强的ccRCC细胞迁移和侵袭。靶向这一新发现的AR-circHIAT1介导的miR-195-5p/29a-3p/29c-3p/CDC42信号可能有助于我们开发潜在的新疗法，以更好地抑制ccRCC转移。
