肿瘤源性外泌体miR-191调控微环境中CAFs的活化促进非小细胞肺癌侵袭转移的机制研究

Tumor-derived exosomal miRNAs are involved in the critical processes in the tumor microenvironment including intercellular communication, the development and progression of cancers. We previously found that the expression of circulating miR-191 was closely related to the risk of tumor progression and death in 522 patients with advanced non-small cell lung cancer (NSCLC), and miR-191 was enriched both in the serum exosomes of patients with early progression and in exosomes of highly invasive NSCLC cell lines. Our preliminary results also suggested that tumor-derived exosomal miR-191 had the potential to activate tumor-associated fibroblasts (CAFs), however, the underlying mechanism of CAFs activation still remains to be explored. Based on our preliminary findings, this proposed study intends to investigate the mechanism of how tumor-derived exosomal miR-191 promotes the invasion and metastasis of NSCLC, and whether miR-191 regulates the expression and activation of LATS1 and its target YAP to promote CAFs activation using cell and animal models and clinical specimens. This study will provide novel insights for the mechanism of invasion and metastasis in NSCLC and provide potential molecular targets for cancer treatment by studying the interaction between tumor cells and the microenvironment.

肿瘤源性外泌体miRNAs在肿瘤微环境中参与细胞间信息传递和肿瘤发生发展等重要过程。前期我们在522例晚期非小细胞肺癌（NSCLC）患者血清中，发现循环miR-191的表达与肿瘤进展和死亡风险密切相关，且miR-191在早期进展患者的血清外泌体及高侵袭NSCLC细胞外泌体中富集。前期结果还提示肿瘤源性外泌体miR-191具有活化肿瘤相关成纤维细胞（CAFs）的潜能，但其具体机制仍有待进一步研究。本课题拟在既有研究基础上从细胞、动物模型及临床肿瘤标本三个层面，研究肿瘤源性外泌体miR-191通过调控微环境中的CAFs活化促进NSCLC侵袭转移的作用，并进一步探究miR-191通过调控LATS1基因及其下游YAP蛋白的表达及活性，促进CAFs活化的机制。本课题将通过研究肿瘤细胞和微环境之间的相互作用，为NSCLC的侵袭转移机制提供新的证据，同时为其治疗提供潜在的分子靶点。

非小细胞肺癌是当今世界上最常见以及最致命的恶性肿瘤之一，其进展迅速，对于晚期NSCLC患者，目前临床上缺少有效的治疗手段。肿瘤源性外泌体miRNAs在肿瘤微环境中参与细胞间信息传递和肿瘤发生发展等重要过程。前期我们在522例晚期非小细胞肺癌（NSCLC）患者血清中，发现循环miR-191的表达与肿瘤进展和死亡风险密切相关，且miR-191在早期进展患者的血清外泌体及高侵袭NSCLC细胞外泌体中富集。前期结果还提示肿瘤源性外泌体miR-191具有活化肿瘤相关成纤维细胞（CAFs）的潜能，但其具体机制仍有待进一步研究。本课题在研究基础上从细胞、动物模型及临床肿瘤标本三个层面，证实:1)肿瘤源性外泌体调控微环境中的CAFs活化，其中miR-191是关键的因子；2) miR-191通过直接结合LATS1基因，转录调控其表达，进而影响LATS1下游YAP蛋白的表达及活性，促进CAFs活化; 3)动物实验提示CAFs中上调miR-191后显著促进肿瘤细胞进展。本课题成功证实了肿瘤源性外泌体促进CAFs活化的一个未曾报道过的分子机制，为NSCLC的侵袭转移机制提供新的证据，同时为其治疗提供潜在的分子靶点。