The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling
The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling
复制标题
Notch 通路通过激活 Ephrin 反向信号传导促进骨肉瘤进展
DOI：
10.1158/1541-7786.mcr-19-0493
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发表时间：
2019-12-01
影响因子：
5.2
通讯作者：
Clarke, Robert B.
中科院分区：
文献类型：
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作者：
Yu, Ling;Xia, Kezhou;Clarke, Robert B.
尽管骨肉瘤的诊断和治疗取得了重大进展，但疾病进展的分子机制仍不清楚。这项工作提供了强有力的临床和实验证据，证明 Notch 信号传导有助于骨肉瘤的进展。首先，通过使用 12 名患者组成的队列，与邻近正常组织相比，Notch 基因在肿瘤中表达上调，Notch1 细胞间结构域 (NICD1) 和 Notch 靶基因 Hes1 的高肿瘤表达与较差的化疗反应相关。对公开数据集的数据挖掘证实，Notch 通路基因的表达与骨肉瘤的不良预后相关。根据体外分析，Notch 信号传导促进骨肉瘤增殖，增强化疗耐药性，促进迁移和侵袭，并上调干细胞样特征。异种移植模型表明，Notch 信号传导促进原发性肿瘤生长和肺转移，而 Notch 抑制可有效减小肿瘤大小并预防转移。从机制上讲，激活的 Notch 信号传导会诱导 ephrinB1 的表达，并增强促进肿瘤的 ephrin 反向信号传导。总体而言，这些发现为Notch通路基因作为预测骨肉瘤患者预后的候选生物标志物提供了功能证据，并提出了使用Notch抑制剂治疗骨肉瘤的机制原理。意义：该研究为Notch通路作为预测骨肉瘤预后的分子标记和作为骨肉瘤的治疗靶点提供了临床前证据。此外，我们还发现了一种新机制，即肝配蛋白反向信号传导充当 Notch 通路的关键介质。
Despite significant advancements in the diagnosis and treatment of osteosarcoma, the molecular mechanisms underpinning disease progression remain unclear. This work presents strong clinical and experimental evidence demonstrating that Notch signaling contributes to osteosarcoma progression. First, using a cohort of 12 patients, Notch genes were upregulated in tumors compared with adjacent normal tissue, and high tumor expression of Notch1 intercellular domain (NICD1) and the Notch target gene Hes1 correlated with poor chemotherapy response. Data mining of publicly available datasets confirmed that expression of Notch pathway genes is related to poor prognosis in osteosarcoma. On the basis of in vitro analysis, Notch signaling promoted osteosarcoma proliferation, enhanced chemoresistance, facilitated both migration and invasion, and upregulated stem cell–like characteristics. Xenograft models demonstrated that Notch signaling promotes primary tumor growth and pulmonary metastasis, and Notch inhibition is effective in reducing tumor size and preventing metastasis. Mechanistically, activated Notch signaling induces the expression of ephrinB1 and enhances the tumor-promoting ephrin reverse signaling. Overall, these findings provide functional evidence for Notch pathway genes as candidate biomarkers to predict prognosis in patients with osteosarcoma, and suggest a mechanistic rationale for the use of Notch inhibitors to treat osteosarcoma. Implications: The study provides preclinical evidence for Notch pathway as a molecular marker to predict osteosarcoma prognosis and as a therapeutic target against osteosarcoma. In addition, we identified a novel mechanism that ephrin reverse signaling acts as a key mediator of Notch pathway.