c-flip表达变化对骨肉瘤肺转移的调控作用及机制研究

Osteosarcoma is the malignant tumor with high propensity for lung metastasis, mainly affecting children and adolescent. Once lung metastasis is occurred, the fatality rate is extremely high. It has been already demonstrated that Fas-procaspases 8/10-mediated apoptotic pathway plays an important role in the lung metastasis of osteosarcoma. Due to high level of FasL in lung tissue microenvironment, tumor cells highly expressing Fas will be eliminated. As the structural homologue of procaspases, c-Flip is capable of inhibiting directly its activation and and inhibits FasL-mediated apoptosis. In our previous research, we found inhibition of c-Flip expression could obviously enhance the sensitivity of osteosarcoma cells to FasL and the expression of c-Flip in lung metastasis was higher than primary lesion revealed by clinical specimens and animal models. Inhibition of c-Flip expression could significantly increase the sensitivity of osteosarcoma to FasL and suppress lung metastasis, possibly correlated with dormancy activation of pulmonary diffusion tumor cells. The proposing project is aimed to solve: 1.confirm the relation between the expression of c-Flip, Fas and lung metastasis of osteosarcoma; 2. investigate the mechanism of c-Flip in regulation of lung metastasis in osteosarcoma; 3. explore the modulation mechanism of differential expression of c-Flip in primary and metastatic lesion. The further investigation of this project will provide theoretical basis for the mechanism of lung metastasis, and also find a novel breakthrough for the therapeutic approaches for preventing osteosarcoma metastasis.

骨肉瘤是一种好发于青少年的恶性肿瘤，极易发生肺转移，一旦转移致死率极高。Fas-procaspases 8/10介导的凋亡途径在骨肉瘤肺转移中有重要作用，肺组织微环境中FasL表达高，故Fas高表达的肿瘤细胞会被清除。c-Flip 作为procaspase 8/10的结构同系物可直接抑制其活化从而抑制Fas介导的肿瘤凋亡。本项目组前期研究发现在临床标本和动物模型中肺转移灶c-Flip表达高于原发灶，抑制c-Flip表达能显著增强骨肉瘤对FsaL的敏感性并抑制肺转移，且可能与肺部扩散肿瘤细胞休眠活化有关。据此，本课题拟通过实验研究解决：1.明确c-Flip和Fas表达与骨肉瘤肺转移的关系；2.研究c-Flip调控骨肉瘤肺转移的作用机制；3.探索原发灶与转移灶c-Flip表达差异的调控机制。本课题的开展期望为骨肉瘤肺转移机制研究提供理论依据，也为抑制肺转移的方法寻找新的突破点。

骨肉瘤好发于青少年，极易发生肺转移，转移致死率极高。Fas-procaspases 8/10介导的凋亡途径在骨肉瘤肺转移中有重要作用，肺组织微环境中FasL表达高，故Fas高表达的肿瘤细胞会被清除。c-Flip 作为procaspase 8/10的结构同系物可直接抑制其活化从而抑制Fas介导的肿瘤凋亡。本项目组研究发现在临床标本和动物模型中肺转移灶c-Flip表达高于原发灶，且c-Flip的原位表达与Fas有一定相关性。进一步研究表明抑制c-Flip表达可通过增强骨肉瘤对FasL的敏感性而减弱骨肉瘤的增殖、迁移、侵袭能力，促进了骨肉瘤的凋亡。且c-Flip与肺部扩散肿瘤细胞休眠活化有关， c-Flip的表达降低可以抑制骨肉瘤肺转移。本课题为骨肉瘤肺转移机制研究提供理论依据，也为抑制肺转移的方法寻找新的突破点。在本项目资助下，我们的研究论文在SCI杂志发表2篇（ Advanced Science, Cancer Letters），在投两篇。