肺癌细胞分泌DKK1重塑骨微环境促进肺癌骨转移的功能和机制研究

Lung cancer is an aggressive malignancy with high morbidity and mortality, and distant metastasis is the leading cause of cancer-related death. Bone is one of the major metastatic sites of lung cancer, which is accompanied by skeletal related events that negatively affect the overall survival and quality of life of lung cancer patients. Bone metastasis of lung cancer is an urgent clinical problem with very limit treatments. DKK1 is a secreted glycoprotein, we previously found that DKK1 was closely associated with bone metastasis and bone microenvironment remolding in lung cancer, and TGF-β may involve as a key molecule. Therefore, we predict that DKK1 secreted by lung cancer cells can be transported to the distal bone to accelerate the remodeling of bone microenvironment by regulating the expression of TGF-β via Wnt/Ca2+ signaling pathway, which in turn promotes lung cancer cells bone metastasis. In this study we firstly aim to further verify the clinical correction between the expression of DKK1 and lung cancer bone metastases with clinical specimens. Then, mouse model of bone metastases and in vitro cell co-culture system will be conducted to reveal the function of DKK1 exert in modulating by using electron microscope, von Kossay and TRAP ect. At last, technology of molecular biology will be applied to validate the mechanism which DKK1 involved in bone microenvironment remolding, additionally, the inhibitors of the pathway and siRNA lentivirus will be used for rescue function experiments in vitro and in vivo. In a word, the goal of this study is to provide a new promising therapeutic target for the prevention and treatment of lung cancer with bone metastasis.

肺癌是发病率和死亡率均很高的肿瘤，远处转移是其主要的死亡原因。骨是肺癌主要的转移部位之一，其伴发的骨相关事件严重影响了肺癌患者的生存期和生活质量。而目前治疗骨转移的药物和手段都不太理想，是目前临床亟待解决的难题。DKK1是一个分泌型糖蛋白，我们前期研究发现DKK1能促进肺癌骨转移和骨微环境重塑，其中TGF-β可能发挥关键作用。因此我们推测肺癌细胞可通过分泌DKK1远端运输到达骨骼，通过Wnt/Ca2+信号通路调控TGF-β的表达，重塑骨骼微环境促进骨转移发生。本项目首先拟通过临床样本进一步明确DKK1与肺癌骨转移的临床相关性；然后通过小鼠骨转移模型和体外细胞共培养系统，运用电镜、von Kossay、TRAP等分析DKK1重塑骨微环境的重要功能；最后利用分子生物学等方法探究其分子机制并通过信号通路抑制剂和siRNA干扰慢病毒进行体内外的回复性功能验证，为肺癌骨转移防治奠定新的理论基础。

肺癌是发病率和死亡率均很高的肿瘤，远处转移是其主要的死亡原因。骨是肺癌主要的转移部位之一，其伴发的骨相关事件严重影响了肺癌患者的生存期和生活质量。而目前治疗骨转移的药物和手段都不太理想，是目前临床亟待解决的难题。DKK1是一个分泌型糖蛋白，我们研究证实DKK1与肺癌骨转移具有临床相关性，同时功能实验进一步证实DDK1促进肺癌骨转移，同时DKK1在肺癌细胞改造骨微环境中发挥重要作用，为肺癌骨转移防治奠定新的理论基础。