胃癌外泌体源性hsa_circ_0015286调控巨噬细胞极化的机制及其分子标志物价值

In tumor microenvironment, exosome derived from gastric cancer (GC) cells mediates tumor progression by regulating the polarization of tumor associated macrophages(TAM). However the detailed mechanism remains elusive. Growing evidences have suggested that circular RNAs enriched in exosome play a pivotal role in cancer progression and can be used as a promising biomarker. Our previous studies showed that hsa_circ_0015286 was enriched in exosome derived from GC cells. Over-expression of hsa_circ_0015286 can induce up-regulation of pNF-κB and promote macrophage polarization towards M2 type, moreover exosomal hsa_circ_0015286 was highly expressed in plasma of GC patients. Based on these findings, we hypothesize that exosomal hsa_circ_0015286 derived from GC cells regulates TAM polarization to promote GC progression, and exosomal hsa_circ_0015286 of plasma could be considered as a promising biomarker for GC. In this study, we will try to elucidate the mechanism of exosomal hsa_circ_0015286 derived from GC cells regulates the polarization of TAM via over-expressed/silenced hsa_circ_0015286 in vitro. Furthermore, we would explore the diagnostic and prognostic potential of plasma exosomal hsa_circ_0015286 in order to provide a novel biomarker and target for GC diagnosis and treatment.

肿瘤微环境中胃癌细胞通过外泌体调控巨噬细胞极化介导肿瘤进展，但具体机制不详。最新研究表明circRNA在外泌体中富集并发挥重要调控作用，同时还是一种理想的生物标志物。我们前期研究发现hsa_circ_0015286在胃癌细胞分泌外泌体中富集，巨噬细胞过表达hsa_circ_0015286后pNF-κB上调，细胞向M2型极化；此外胃癌患者血浆外泌体源性hsa_circ_0015286水平显著升高。因此提出假设胃癌细胞通过外泌体传递hsa_circ_0015286诱导巨噬细胞极化进而促进胃癌进展；同时释放入血的外泌体源性hsa_circ_0015286可作为胃癌新型标志物。本项目拟通过体外过表达/沉默等一系列实验明确hsa_circ_0015286调控巨噬细胞极化的分子机制，并探讨血浆外泌体源性hsa_circ_0015286作为胃癌分子标志物的应用价值，以期为胃癌诊疗提供新标志物和新靶标。

肿瘤微环境中胃癌细胞与巨噬细胞之间可通过外泌体传递信号分子相互调控介导肿瘤进展，同时外泌体内所包含RNA还可进入外周循环成为肿瘤诊断的有效分子标志物。本项目研究发现与慢性胃炎及健康对照组相比较，胃癌患者血浆外泌体源hsa_circ_0015286和lnc-SLC2A12-10:1表达水平显著升高，ROC曲线分析表明其单指标用于胃癌诊断的效能优于CEA、CA19-9，多种指标联合诊断的效能优于各项单指标及两项指标联合检测。此外血浆外泌体源hsa_circ_0015286表达水平与胃癌组织中表达呈正相关，术后表达水平显著降低；通过分析患者临床病理资料，发现血浆外泌体源hsa_circ_0015286的高表达与肿瘤分期、分化程度以及淋巴结转移等有关，表明其还有可能成为胃癌患者疗效监测和预后评估的有效指标。细胞机制研究表明一方面胃癌细胞外泌体源hsa_circ_0015286通过调控NF-κB信号通路诱导巨噬细胞M2型极化。另一方面巨噬细胞通过外泌体传递miR-223至胃癌细胞，通过调控EMT转化促进胃癌细胞的侵袭和对多柔比星的耐药。