申请人前期研究发现血清NSE水平与小细胞肺癌（SCLC）患者脑转移成正相关；沉默NSE表达能抑制SCLC细胞的侵袭和上皮间质化过程，并下调ALDH+肺癌干细胞（CSC）百分比，CSC是肿瘤转移的根源，我们提出NSE能增强CSC干性作用从而促进SCLC脑转移的假说。目前关于NSE增强CSC干性作用尚不清楚。本课题利用siRNA干扰NSE后，首先明确肿瘤微环境中NSE能增强CSC干性作用（增殖、成瘤性及转移性等）；研究NSE增强CSC干性作用的信号通路（包括PI3K/Akt/mTOR和Wnt/β-catenin）及下游干细胞基因；进一步研究NSE促进CSC发生脑转移的趋化因子/趋化因子受体通路。本课题探索NSE促进SCLC脑转移的新机制，为治疗SCLC脑转移提供新的靶点。

Our previous study demonstrated that there was positive correlation between the serum NSE concentrations and brain metastasis of small cell lung cancer (SCLC) patients. Silence of NSE prevented the migration and epithelial-mesenchymal transition (EMT), and decreased the percentage of ALDH+ cancer stem cells (CSC). CSC was the origin of tumor metastasis. Thus, we hypothesized that NSE could promote the brain metastasis through enhancing stemness of SCLC CSCs. However, there was no report concerning the effect of NSE on CSCs. This project will study the effect of NSE on the stemness of CSC, including self-renewal, tumorigenicity and metastasis. Then we will evaluate whether NSE could enhance the stemness of CSCs through activating PI3K/Akt/mTOR and Wnt/β-catenin pathways and explore the downstream CSC related genes. By establishing brain metastasis mice model, we will explore the chemokines and chemokine receptors which could lead to the brain metastasis of CSCs. By studying the effect and mechanism of NSE-promoted brain metastasis through enhancing ALDH+CSC stemness, it could provide a novel target to specifically target SCLC brain metastasis.