27-羟基胆固醇在肺腺癌转移中的作用机制研究

27-羟基胆固醇在心血管疾病、肥胖和炎症反应中起着重要作用。近期，27-羟基胆固醇被证实通过激活肝X受体(LXR)促进乳腺癌转移。我们发现27-羟基胆固醇同样能够促进肺腺癌细胞迁移，但并不是完全依赖于LXR的激活。27-羟基胆固醇作用肺腺癌细胞同时促进了LXR和法尼酯衍生物X受体（FXR）的表达上调。基于此，本课题拟通过体内体外敲除或过表达LXR和/或FXR，在提高和降低27-羟基胆固醇浓度的条件下，研究LXR和FXR在27-羟基胆固醇调节肺腺癌转移中的作用，明确27-羟基胆固醇在肺腺癌转移中的作用机制，确定27-羟基胆固醇在高胆固醇血症与肺腺癌转移中的侨联作用。通过本课题的研究，不仅能明确27-羟基胆固醇在肺腺癌转移中的作用机制，为治疗肺腺癌转移提供新的靶点，还有助于揭示高胆固醇血症与肺腺癌转移的关系，对预防和治疗肺腺癌转移具有重要意义。

27-hydroxycholesterol plays important roles in cardiovascular disease,obesity and inflammation. Recently, 27-hydroxycholesterol was demonstrated to promote metastasis of breast cancer by activating liver X receptor (LXR). We found that 27-hydroxycholesterol also facilitated migration of lung adenocarcinoma, which was not totally dependent on LXR. Treatment of lung adenocarcinoma cells with 27-hydroxycholesterol up-regulated LXR and farnesoid X receptor (FXR) in a parallel manner. Based on these results, in this project, under elevated or reduced concentration of 27-hydroxycholesterol, it would be explored whether LXR and FXR play key roles in 27-hydroxycholesterol-induced metastasis of lung adenocarcinoma by single or double knockout of LXR and FXR, which could contribute to clarify the regulatory mechanism of 27-hydroxycholesterol in metastasis of lung adenocarcinoma. It would be confirmed whether 27-hydroxycholesterol links hypercholesterolemia and metastasis of lung adenocarcinoma. The data from this study not only validated the function of 27-hydroxycholesterol in mediating metastasis of lung adenocarcinoma, providing novel targets for treating lung adenocarcinoma metastasis, revealing the relation between hypercholesterolemia and lung adenocarcinoma metastasis, which would be significant for prevention and treatment of lung adenocarcinoma metastasis.