Notch3 pathway alterations in ovarian cancer.
Notch3 pathway alterations in ovarian cancer.
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DOI：
10.1158/0008-5472.can-13-2066
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发表时间：
2014-06-15
期刊：
影响因子：
11.2
通讯作者：
Sood AK
中科院分区：
文献类型：
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作者：
Hu W;Liu T;Ivan C;Sun Y;Huang J;Mangala LS;Miyake T;Dalton HJ;Pradeep S;Rupaimoole R;Previs RA;Han HD;Bottsford-Miller J;Zand B;Kang Y;Pecot CV;Nick AM;Wu SY;Lee JS;Sehgal V;Ram P;Liu J;Tucker SL;Lopez-Berestein G;Baggerly KA;Coleman RL;Sood AK
Notch通路在高级别浆液性卵巢癌（HGS-OvCa）和其他癌症的生长中发挥着重要作用，但其临床和生物学机制尚不清楚。在这里，我们发现 Notch 通路的改变很普遍，并且与卵巢癌患者不良的临床结果显着相关。特别是，Notch3 的改变，包括扩增和上调，与患者生存率低下高度相关。靶向 Notch3 可抑制 OvCa 生长并诱导细胞凋亡。重要的是，我们发现 DNM 介导的内吞作用是选择性激活 Jagged-1 介导的 Notch3 信号传导所必需的。剪切的Notch3表达是Notch靶向治疗反应的关键决定因素。总的来说，这些数据确定了以前未知的 Notch3 信号传导机制，并确定了新的、生物标志物驱动的治疗方法。
Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biological 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 OvCa growth and induced apoptosis. Importantly, we found that DNM-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.