p68调控Notch信号途径在肺腺癌干细胞自我更新中的作用及机制研究

Cancer stem cells are believed to be the basis of tumor occurrence, metastasis, recurrence, and resistances to both chemo- and radio-therapy. Deeper understanding of the mechanism of self-renweal in cancer stem cells might provide novel strategies for anticancer therapy. Previously, we have successfully identified and isolated lung adenocarcinoma stem cells, and observed significantly elevated expression of p68 in lung adenocarcinoma stem cells, as compared to lung adenocarcinoma cells. Notch pathway plays an important role in cancer stem cell maintenance, and prior studies have shown that p68 might be a positive regulator of Notch signaling. In combination with the recent progresses in the field of cancer stem cells, we hypothesized that p68/Notch pathway might be aberrantly activated, and played an important role in the maintenance of stem cell-like properties of lung adenocarcinoma stem cells, which further contributed to tumorigenicity. In this project, we planned to first evaluate the transcription and expression levels of p68 and Notch signaling using RT-PCR and immunohistochemical analysis. Second, we would establish p68 over-expression lung adenocarcinoma cells and low-expression lung adenocarcinoma stem cells, and further study the role of p68 in the self-renewal of lung adenocarcinoma stem cells, by cyclin detection and mouse tumorigenic experiments. The findings might bring new targets for lung adenocarcinoma stem cells-targeted therapy.

肺腺癌干细胞被认为是肺腺癌发生、转移和复发的根源，深入研究其自我更新的生物学机制将为临床诊疗提供新思路。在前期工作中我们发现：重要的核转录因子p68在肺腺癌干细胞中呈高表达，而敲低p68表达水平可显著降低其自我更新能力，提示p68在肺腺癌干细胞自我更新维持中可能具有重要作用；结合p68的信号通路及肺腺癌干细胞维持自我更新的分子机制，我们推测：p68可能通过调控Notch信号途径参与肺腺癌干细胞的自我更新。本课题组拟采用定量RT-PCR、免疫荧光等方法检测比较肺腺癌干细胞和肺腺癌细胞中p68、Notch通路信号分子的转录、表达；利用慢病毒转染、siRNA干扰等分别构建p68过表达肺腺癌细胞和p68低表达肺腺癌干细胞，通过成球实验、小鼠致瘤实验等方法，研究p68在肺腺癌干细胞自我更新维持中的调控作用及机制。研究结果有望进一步揭示肺腺癌干细胞自我更新的分子机制，为肺腺癌的临床诊疗提供新靶点。

肺癌干细胞被认为是肺癌发生，转移和复发的根源，本研究在前期工作中发现RNA解旋酶p68在肺癌干细胞样细胞中呈高表达，运用WB，流式分析，成球实验，迁徙试验，小鼠成瘤试验等方法技术，证实了p68在肺癌细胞干性调控中发挥了重要作用，同时发现在p68过表达的肺癌细胞系中，Akt通路异常激活，其下游靶蛋白ENTPD5表达亦上调。提示p68对肺癌细胞干性调控是通过Akt-ENTPD5信号轴来实现的，为肺癌的诊治提供了新的靶点及思路。

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