肺癌骨转移患者生存率低，有效治疗药物少。近年来发现他汀类药物有广泛抗癌作用，且与双膦酸盐作用机制相似，有望成为新的骨转移癌治疗药物。前期研究提示他汀类药物能抑制肺癌细胞迁移及侵袭，并诱导细胞自噬，其中自噬底物蛋白P62是关键调节蛋白之一,但他汀类药物是否通过下调P62蛋白表达抑制肺癌细胞转移不明确。本研究采用Westernblot检测肺癌细胞经他汀类药物处理后，P62、mTOR1及NF-κb蛋白水平变化，明确他汀类药物是否依赖P62蛋白调节及相关信号传导通路；然后质粒转染上调、shRNA干扰下调P62蛋白表达后，采用划痕实验、基底膜侵袭实验测他汀类药物抑制肺癌细胞迁移及侵袭的变化；最后于溶骨性转移小鼠模型心内注射shRNA P62肺癌细胞，运用活体成像及CT成像，评价下调P62蛋白表达对他汀类药物抗癌作用的影响，并对骨转移组织行流式检测、免疫组化及TRAP染色，分析其抑制肺癌骨转移的机制

Five-year relative survival of lung cancer bone metastasis was less than 5%, and it was lack of effective treatment medicine. Recently it was showed statins had wide antitumor activity.Also statins had bisphosphonate-like manner by preventing mevalonate production, it probably becomes a new kind of medicine for bone metastasis treatment. We previously revealed statins could inhibit tumor migration and invasion of lung adenocarcinoma and induce autophagy leading to metabolic stress, where P62 protein may be one of key functional protein. P62 protein is a substrate of autophagy, and autophagy could degrade p62 protein. But whether statins could induce autophagy by downregulating P62 protein was not clear. Meawhile, latest research showed P62 protein could activate nuclear factor-κb(NF-κb), increasing bone-resorption of osteoclast,causing osteolytic metastasis finally.So downregulation of P62 protein could inhibit bone metastasis, but whether statins depend on P62 protein regulation was not clear. In this study firstly expression of P62 mRNA and protein after statins incubation on lung adenocarcinoma cell SPC-A-1 and A549 were assessed by RT-PCR and westernblot assay.Secondly we upregulate P62 protein expression by plasmid transfection or downregulate P62 protein expression by short hairpin RNA interferrence(shRNA) of lung adenocarcinoma cell SPC-A-1 and A549, and detect tumor migration ang invasion by Transwell migration assay and Matrigel invasive assay after statins incubation. Meanwhile we analyse P62, mTOR1, LC3Ⅱ/Ⅰptotein expression,activation of NF-κb by Electrophoretic mobility shift assay(EMSA) to explore possible signal channel of statins function. Finally we inject shRNA lung adenocarcinoma cell SPC-A-1 to ventriculus sinister of rat osteolytic metastasis model, then evaluate antitumor effect of statins by bioluminescence imaging and X-ray/CT imaging; and discuss the molecular mechanism by flow cytometry analysis, counting osteoclast number with TRAP staining and immunohistochemical staining, to offer new theory evidence for clinical treatment of lung cancer bone metastasis.