CD73通过非腺苷途径活化整合素激活TGF-β/Smad信号通路促进非小细胞肺癌转移的机制研究

转移复发是非小细胞肺癌（NSCLC）患者死亡的主要原因，发现转移关键分子并探索其作用机制，对降低死亡率具有重要意义。CD73是一种70kDa的多功能跨膜糖蛋白，在多种恶性肿瘤中高表达。研究表明CD73可通过腺苷途径负性调控免疫细胞和非腺苷途径调控细胞与细胞外基质相互作用，介导肿瘤的侵袭和转移，但肺癌中未见报道。我们前期研究发现CD73在NSCLC中高表达。进一步干扰CD73后，可显著抑制外源性TGF-β1诱导的肿瘤细胞迁移和侵袭；通过腺苷通路抑制剂APCP和蛋白芯片检测发现，CD73非腺苷途径中整合素发挥着重要作用。因此，我们提出假说：除腺苷途径外，CD73可通过整合素激活TGF-β/Smad通路进而促进NSCLC发生EMT及转移。本项目拟通过多种实验手段，阐明CD73非腺苷途径通过整合素调控TGF-β/Smad通路促进NSCLC转移的详细调控机制，为肺癌精准治疗寻找新的靶点提供理论依据。

Metastasis and recurrence are the main causes of death in NSCLC. It is of great significance to find out the key molecules of metastasis and explore their mechanism. CD73 is a 70 kDa multifunctional glycosylphosphatidylinositol, which is highly expressed in many kinds of malignant tumors. It has been shown that CD73 can impairs adaptive anti-tumor immune responses through its ecto-enzymatic activity. Moreover, CD73 also functions as a signal and adhesive molecule that can regulate cell interaction with extracellular matrix components, such as laminin and fibronectin, to mediate the invasive and metastatic properties of cancers. However, the role of CD73 in lung cancer remains unclear. In our previous study, we found that CD73 was highly expressed in NSCLC. Further, knockdown of CD73 could significantly inhibit the migration and invasion of tumor cells under the stimulation of TGF-β1. Interestingly, we found that CD73 promotes EMT in lung squamous cell carcinoma independent of its enzyme activity through the APCP and Protein Array. Therefore, we propose the hypothesis that CD73 can activate TGF-β/Smad pathway promoting EMT and metastasis of NSCLC through integrins. This project intends to clarify the detailed regulatory mechanism of CD73 non-adenosine pathway regulating TGF-β/Smad pathway to promote NSCLC metastasis through integrin, and provides new insight into therapy strategies for NSCLC.