He Chunbo, Mao Dagan, Hua Guohua, Lv Xiangmin, Chen Xingcheng, Angeletti Peter C, Dong Jixin, Remmenga Steven W, Rodabaugh Kerry J, Zhou Jin, Lambert Paul F, Yang Peixin, Davis John S, Wang Cheng
Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China.
Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.
EMBO Mol Med. 2015 Nov;7(11):1426-49. doi: 10.15252/emmm.201404976.
The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer.
河马信号通路通过使Yes相关蛋白（YAP）失活的激酶级联反应来控制器官大小和肿瘤发生。在此，我们表明YAP在控制宫颈癌进展中起核心作用。我们的结果表明YAP表达与宫颈癌的不良预后相关。转化生长因子-α（TGF-α）和双调蛋白（AREG）通过表皮生长因子受体（EGFR）抑制河马信号通路并激活YAP，以诱导宫颈癌细胞增殖和迁移。激活的YAP可上调TGF-α、AREG和EGFR，形成一个正向信号环以驱动宫颈癌细胞增殖。人乳头瘤病毒E6蛋白是宫颈癌的主要致病分子，它通过阻止蛋白酶体依赖性的YAP降解来维持宫颈癌细胞中YAP蛋白的高水平，从而驱动宫颈癌细胞增殖。来自人类宫颈癌基因组数据库和公认的转基因小鼠模型的结果有力地支持了所发现的前馈信号环的临床相关性。我们的研究表明，联合靶向河马信号通路和ERBB信号通路代表了一种预防和治疗宫颈癌的新型治疗策略。
