Zhang Dongmei, Zhang Gao, Hu Xiaowen, Wu Lawrence, Feng Yi, He Sidan, Zhang Youyou, Hu Zhongyi, Yang Lu, Tian Tian, Xu Weiting, Wei Zhi, Lu Yiling, Flaherty Keith T, Zhong Xiaomin, Mills Gordon B, Gimotty Phyllis A, Xu Xiaowei, Herlyn Meenhard, Zhang Lin
Department of Gynecology and Obstetrics, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Center for Research on Reproduction & Women's Health, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Res. 2017 Jul 15;77(14):3745-3757. doi: 10.1158/0008-5472.CAN-16-1768. Epub 2017 May 4.
RAS and its downstream cascades transmit cellular signals, resulting in increased transcription of genes involved in cell growth and division. Protein-coding gene targets of RAS signaling have been characterized extensively, but long noncoding RNAs (lncRNA) regulated by these processes have not. Using a custom-designed lncRNA microarray, we identified the lncRNA as a genetic target of RAS that is critical for RAS oncogenicity. expression was regulated by RAS-RAF-MEK-ERK signaling via the transcription factor AP1. was highly expressed in BRAF-mutant cancers, such as melanoma. Silencing of blocked tumor cell proliferation and growth and In addition, blockade reduced expression of cyclin E1 and induced G-S cell-cycle arrest in tumor cells. Taken together, our results identify as a novel, nonprotein mediator of RAS/RAF activation that may serve as a therapeutic target in RAS/RAF-driven cancers. .
RAS及其下游级联反应传递细胞信号,导致参与细胞生长和分裂的基因转录增加。RAS信号传导的蛋白质编码基因靶点已得到广泛表征,但受这些过程调控的长链非编码RNA(lncRNA)尚未得到充分研究。我们使用定制设计的lncRNA微阵列,将lncRNA鉴定为RAS的一个基因靶点,它对RAS致癌性至关重要。其表达通过转录因子AP1受RAS-RAF-MEK-ERK信号传导调控。它在BRAF突变型癌症(如黑色素瘤)中高度表达。沉默该lncRNA可阻断肿瘤细胞增殖和生长,此外,阻断该lncRNA可降低细胞周期蛋白E1的表达,并诱导肿瘤细胞发生G-S期细胞周期阻滞。综上所述,我们的结果确定该lncRNA是RAS/RAF激活的一种新型非蛋白质介质,可能成为RAS/RAF驱动癌症的治疗靶点。