黑素瘤占全部皮肤肿瘤致死病例的75%，其在我国的发病率正快速增长。研究发现，Notch信号通路在黑素瘤发生发展中起着重要的作用，然而，该通路是通过何种机制影响黑素瘤的恶性行为尚未得到完整地阐释。近年研究证实：多种细胞中，Notch通路与细胞衰老逃逸（CSE）和上皮间充质转化（EMT）密切相关，对二者关键通路分子及诱导因子存在多水平的调控。CSE和EMT是肿瘤细胞两个重要的恶性生物学行为，且二者密切相关。我们的前期研究发现：黑素瘤患者的肿瘤细胞存在Notch通路的异常活化；抑制Notch通路可诱导黑素瘤细胞出现衰老表型并影响EMT表型。提示Notch通路可能是黑素瘤细胞衰老和EMT的关键调控分子。本课题拟通过Notch对黑素瘤CSE及EMT的作用研究，明确Notch对黑素瘤恶性行为的影响。期望通过对Notch通路的调控，实现诱导黑素瘤细胞衰老和EMT逆转，为黑素瘤的新治疗策略提供理论依据。

Notch signaling pathway is believed to be of great potential in tumor development. This point is supported by findings of its oncogenic role in various tumor cells including melanoma. Since Notch signaling pathway has been proven to be an important regulator of cellular senescence and Epithelial to Mesenchymal Transition(EMT), it leads us to a hypothesis that its activation in melanoma may be responsible, at least partially, of senescence escape and EMT of melanoma cells. To testify this hypothesis, we detected senescence phenotypes in melanoma cells after treatment of GSI, a selective γ-secretase inhibitor, as a classic blocker of Notch signaling. Our preliminary experiments revealed the senescence- inducing ability of GSI in melanoma cells. To further identify the underlying regulation mechanism of Notch signaling pathway in melanoma, we plan to characterize the signaling events in response to Notch signaling in vitro and in vivo. We believe that understanding the role of Notch signaling pathway in senescence escape and EMT of melanoma may lead to the identification of novel targets for therapeutic interventions.