Hu Wei, Liu Tao, Ivan Cristina, Sun Yunjie, Huang Jie, Mangala Lingegowda S, Miyake Takahito, Dalton Heather J, Pradeep Sunila, Rupaimoole Rajesh, Previs Rebecca A, Han Hee Dong, Bottsford-Miller Justin, Zand Behrouz, Kang Yu, Pecot Chad V, Nick Alpa M, Wu Sherry Y, Lee Ju-Seog, Sehgal Vasudha, Ram Prahlad, Liu Jinsong, Tucker Susan L, Lopez-Berestein Gabriel, Baggerly Keith A, Coleman Robert L, Sood Anil K
Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2014 Jun 15;74(12):3282-93. doi: 10.1158/0008-5472.CAN-13-2066. Epub 2014 Apr 17.
The Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biologic mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited ovarian cancer growth and induced apoptosis. Importantly, we found that dynamin-mediated endocytosis was required for selectively activating Jagged-1-mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy.
Notch信号通路在高级别浆液性卵巢癌（HGS-OvCa）及其他癌症的生长中起重要作用，但其临床和生物学机制尚未完全明确。在此，我们发现Notch信号通路改变在卵巢癌患者中普遍存在，且与不良临床结局显著相关。特别是，Notch3改变，包括扩增和上调，与患者生存率低高度相关。靶向Notch3可抑制卵巢癌生长并诱导细胞凋亡。重要的是，我们发现发动蛋白介导的内吞作用是选择性激活Jagged-1介导的Notch3信号所必需的。切割的Notch3表达是对Notch靶向治疗反应的关键决定因素。总体而言，这些数据揭示了Notch3信号传导背后以前未知的机制，并确定了新的、由生物标志物驱动的治疗方法。
