IL-7/IL-7R对肺癌细胞自噬的调节作用及分子机制研究

We found that Interleukin 7(IL-7)/IL-7 receptor (IL-7R) regulated proliferation and apoptosis of lung cancer cell and tumor lymphangiogenesis by different signaling pathways.Blocking IL-7R was able to inhibit tumor growth and metastasis through inhibiting the proliferation of tumor cells, promoting the apoptosis of tumor cells and inhibiting lymphangiogenesis. The inhibition of IL-7R inhibited development and metastasis of lung cancer by multiple signaling pathways and key points. At the same time,we found that the expression rate of IL-7R in non-small cell lung cancer( NSCLC) tumor cells is 62%. By immunohistochemical staining we found that IL-7/IL-7R expression levels with Beclin-1 expression were negative correlation. So we assume that IL-7/IL-7R may regulate the autophagy of lung cancer cells via mTOR, Beclin 1 and/or p53 signal pathways. We will detect the mechanism and effect of IL-7/IL-7R regulating autophagy in vitro. We will discuss whether blocking IL-7R can induce autophagic cell death in lung cancer. Thus, IL-7R may become a new therapeutic targeting against lung cancer.

我们前期研究显示，IL-7/IL-7R可以通过不同的信号通路调控肺癌细胞的增殖和凋亡及肿瘤淋巴管新生，而阻断IL-7R可以抑制肿瘤细胞增殖，促进肿瘤细胞凋亡，抑制淋巴管形成，从而抑制肿瘤生长和转移。抑制IL-7R可以从多个信号通路和关键点抑制肺癌发展和转移。而且我们研究发现有62%的NSCLC肿瘤细胞有IL-7R的表达。我们利用免疫组化方法检测发现肺癌组织中IL7/IL-7R与自噬相关蛋白Beclin-1负相关。因此我们推测IL-7/IL-7R可能调控肺癌细胞自噬， IL-7/IL-7R可能通过mTOR、Beclin 1和p53信号通路三条之一或共同调控肺癌细胞自噬。我们项目组拟通过体外实验验证IL-7/IL-7R调控肺癌细胞自噬的效应,及其调控机制。通过进一步研究阻断IL-7R是否引起肺癌细胞自噬性死亡，探讨IL-7R作为新的治疗靶点的可行性。

前期我们发现IL-7/IL-7R可以通过不同的信号通路调控肺癌细胞的增殖和凋亡及肿瘤淋巴管新生，而阻断IL-7R可以抑制肿瘤细胞增殖，促进肿瘤细胞凋亡，抑制淋巴管形成，从而抑制肿瘤生长和转移。抑制IL-7R可以从多个信号通路和关键点抑制肺癌发展和转移。本项目探讨IL-7/IL-7R与自噬的关系。我们通过免疫组化方法研究了100例非小细胞肺癌组织中IL-7、IL-7R与自噬相关蛋白Beclin 1与和mTOR的表达情况，结果发现Beclin 1与IL-7、IL-7R和mTOR明显负相关，而mTOR与IL-7和IL-7R明显正相关；Cox回归分析显示mTOR高表达和/或Beclin 1低表达提示预后不良。我们项目组通过电镜实验发现IL-7/IL-7R可以抑制自噬，随后通过体外细胞实验发现，IL-7/IL-7R可以通过不同的通路抑制自噬。IL-7/IL-7R通过抑制Beclin 1的表达，激活PI3K/AKT/mTOR通路，抑制自噬；IL-7/IL-7R也可通过诱导P53从细胞核进入细胞质调控AMPK/mTOR通路，从而抑制自噬。