脂肪酸受体CD36对烟草致癌物NNK诱导肺癌α7nAChR信号通路的调控

脂肪酸受体CD36可促进肿瘤细胞摄取脂肪酸进而满足肿瘤细胞增殖和转移的能量需要。但CD36在烟草致癌物NNK通过其膜受体α7nAChR诱导肺癌细胞生成、转移中的作用与机制尚不明确。我们前期研究表明，CD36在吸烟肺癌患者的癌组织、NNK诱导小鼠的肺癌组织及NNK处理的肺细胞中表达增加，并且CD36在细胞膜上分布增多。CD36敲低后可显著抑制NNK经α7nAChR诱导的细胞增殖、转移及相关激酶的活性。因此我们提出细胞膜上分布的CD36除转运脂肪酸外，还具有介导细胞信号转导的作用，进而调控NNK的致癌效应。本项目拟用野生和CD36-/-型A/J小鼠、裸鼠、肺上皮和肺腺癌细胞为模型，于正常和高脂条件下通过基因敲除、抑制剂阻断等方法，阐明CD36对NNK诱导肺癌α7nAChR信号通路的调控机制，并揭示血液中可溶性CD36与肺癌组织中CD36的相关性，为诊断和治疗吸烟导致的肺癌提供有价值的靶点。

Fatty acid receptor CD36 can promote the uptake of fatty acids by tumor cells to meet the energy needs of tumor cell proliferation and migration. However, the role and mechanism of CD36 in the induction of lung cancer cell formation and metastasis by NNK through its membrane receptor α7nAChR are not clear. Our previous studies showed that CD36 expression increased in the lung cancer tissues of smoking lung cancer patients, NNK-induced lung cancer tissues of mice and NNK treated lung cells, and CD36 distribution increased on the cell membrane. CD36 knockdown significantly inhibited NNK-induced cell proliferation, metastasis and related kinases activity via α7nAChR. Therefore, we suggest that CD36 on the cell membrane not only transports fatty acids, but also induces intracellular signal transduction, thus regulating the carcinogenic effect of NNK. In this project, wild-type and CD36-/- A/J mice, nude mice and lung epithelial and lung adenocarcinoma cells will be used to study the key role of CD36 in the regulation of NNK-induced α7nAChR signal pathway in lung cancer, by gene knock out and inhibitor blocking et al under normal and high-fat conditions. The correlation between soluble CD36 in blood and CD36 in lung cancer tissue will be explored at the same time. This study may provide valuable targets for the diagnosis and treatment of lung cancer caused by smoking.