25羟基胆固醇在肺腺癌骨转移中的作用机制研究

肺腺癌骨转移是肺腺癌高死亡率的主要原因。我们已经证实，25羟基胆固醇既能诱导破骨细胞分化，又能促进肺腺癌细胞迁移和侵袭，但在肺腺癌骨转移中的作用机制还未被阐明。25羟基胆固醇能够激活肝X受体（LXR），但抑制LXR表达并没有完全阻断25羟基胆固醇的作用。肺腺癌细胞特异表达雌激素受体beta（ERβ），25羟基胆固醇可能是ERβ选择性激活剂。我们的预实验结果显示，25羟基胆固醇调节的大部分下游分子启动子具有ERβ结合位点。基于此，本课题拟通过敲除或过表达LXR和/或ERβ，在提高或降低25-羟基胆固醇浓度的条件下，研究LXR和ERβ在25羟基胆固醇调节肺腺癌骨转移中的作用，明确25羟基胆固醇在肺腺癌骨转移中的作用机制，同时为治疗肺腺癌骨转移提供新的靶点，对预防和治疗肺腺癌骨转移具有重要的理论和现实意义。

Bone metastasis of lung adenocarcinoma is the main cause of high mortality of lung adenocarcinoma.We have demonstrated that 25-hydroxycholesterol can not only induce osteoclast differentiation, but also promote the migration and invasion of lung adenocarcinoma cells, but the functional mechanism of the bone metastasis of lung adenocarcinoma has not been elucidated. 25-hydroxycholesterol can activate the liver X receptor (LXR), but inhibition of LXR does not completely block the effect of 25-hydroxycholesterol. Lung adenocarcinoma cells specifically express estrogen receptor beta (ERβ), and 25-hydroxycholesterol might be a selective activator of ERβ. Our preliminary results showed that the promoters of most downstream molecular regulated by 25-hydroxycholesterol have ERβ binding sites. Based on the above findings, in this project, we aim to investige the roles of LXR and ERβ in regulating the function of 25-hydroxycholesterol in bone metastasis of lung adenocarcinoma, via knockout or overexpression of LXR and/or ERβ, under the condition of increasing or decreasing the concentration of 25-hydroxycholesterol. This study would clarify the functional mechanism of 25-hydroxycholesterol in the bone metastasis of lung adenocarcinoma, and provide novel targets for treatment of bone metastasis from lung adenocarcinoma, which would be theoretically and realistically significant for the prevention and treatment of bone metastasis from lung adenocarcinoma.