肿瘤前转移微环境中miRNA的功能研究

It is rapidly becoming evident that the formation of tumor-promoting pre-metastatic niches in secondary organs adds a previously unrecognized degree of complexity to the challenge of curing metastatic disease. Numerous studies have described the altered expression and the causal role of microRNAs (miRNAs) in human cancer. However, to date, the function of miRNAs in pre-metastatic niches has not been revealed. Based on our findings of pulmonary vascular destabilization in pre-metastatic niches, we will identify the miRNA signature in pre-metastatic lungs of B16 tumor bearing mice. We will also explore the function of specific miRNAs in pre-metastatic lungs, especially in the process of pulmonary vascular destabilization and BMDC recruitment. Furthermore, we will illuminate the targets of specific miRNAs and investigate their roles in pre-metastatic lungs.

近年来，肿瘤前转移被发现在恶性肿瘤转移过程中起着关键作用，研究肿瘤前转移微环境将有助于进一步了解肿瘤转移，为转移的预防和治疗提供新思路。我们曾报道在癌细胞转移前，黑色素瘤原发灶通过特异上调远端肺部3个基因（血管生成素2、基质金属蛋白酶3和10）使血管渗漏，有助于癌细胞侵出实现转移。miRNA参与多种癌症的转移。我们最近报道，miRNA可以靶向在肺部前转移过程中起关键调控作用的血管生成素2，进而增强血管稳定性，抑制血管新生。鉴于目前尚未见miRNA在前转移方面的报道,本课题将在肿瘤前转移模型中研究miRNA表达谱，筛选出关键miRNA，并围绕前转移环境中的血管通透性和骨髓源细胞招募两方面深入探索关键miRNA的功能和作用机理。进而，我们将鉴定关键miRNA的作用靶点，研究相关靶点对前转移环境的调控作用，深入阐明肿瘤前转移环境形成的分子机制，为靶向肿瘤前转移的肿瘤治疗奠定理论基础。

我们确认了miRNA在黑色素瘤在肺部前转移中的作用，其中肺部成纤维细胞分泌的miR-30s可以稳定肺部的血管。通过在肺部过表达miR-30s可以显著减少接种黑色素瘤的小鼠转移灶，并提高小鼠的生存率；通过后续的机理研究，我们发现Skp2蛋白是miR-30s的重要下游因子，过表达Skp2可以破话肺部的血管进而促进肿瘤转移和降低小鼠的生存期。