肿瘤相关成纤维细胞通过分泌外泌体miR-146a-5p促进膀胱癌干性维持的实验研究

Cancer-associated fibroblasts (CAFs) are involved in the formation of tumor microenvironment during cancer development. CAFs are thought to play essential roles in promoting cancer cell stmeness. However, how CAFs regulate cancer cells, especially the maintenance of cancer cell stemness, remains unclear. We found that CAFs induce stemness maintenance of bladder cancer through secreting exosomes, in which miR-146a-5p is the key molecule. Hence, We propose the hypothesis that CAFs promote stemness maintenance of bladder cancer via secreting exosomal miR-146a-5p. At first, we plan to testify the stemness promoting function of paracrine exosomes from CAFs. Furthermore, we will confirm whether exosomal miR-146a-5p promotes bladder cancer cell stemness. Moreover, we will test the downstream target gene of miR-146a-5p and relative signalling pathway, to explain the molecular mechanism of miR-146a-5p function. At last, we will explore the clinical application of exosomal miR-146a-5p from patients’ body fluid. Taken together, this research will reveal how the exosomal miR-146a-5p secreted by CAFs induce cancer cell stemness and examine whether exosomal miR-146a-5p is a potential drug target for bladder cancer.

肿瘤相关成纤维细胞参与肿瘤微环境并影响肿瘤干性维持，但其分子机制现在了解甚少。我们以膀胱癌为研究对象，发现由肿瘤相关成纤维细胞分泌的外泌体介导了对膀胱癌细胞的干性维持作用，同时外泌体中的miR-146a-5p是促进膀胱癌细胞干性能力的关键分子。因此，我们提出肿瘤相关成纤维细胞通过分泌外泌体miR-146a-5p促进膀胱癌干性维持。首先，我们将在体内和体外实验中确认肿瘤相关成纤维细胞对膀胱癌的干性维持作用是通过外泌体介导；其次，我们将通过实验验证外泌体miR-146a-5p对膀胱癌干性维持的促进作用；再者，筛选miR-146a-5p的下游靶基因和信号通路，分析其促进干性能力的分子机制；最后，检测病人体液中的miR-146a-5p，探索其预测膀胱癌和指导预后的临床应用。本研究将充分阐述外泌体miR-146a-5p介导的肿瘤相关成纤维细胞对于肿瘤细胞干性维持的分子机理，也为膀胱癌的治疗提供靶点。

肿瘤相关成纤维细胞参与肿瘤微环境并影响肿瘤干性维持，但其分子机制现在了解甚少。我们以膀胱癌为研究对象，发现由肿瘤相关成纤维细胞分泌的外泌体介导了对膀胱癌细胞的干性维持作用，同时外泌体中的miR-146a-5p是促进膀胱癌细胞干性能力的关键分子。本项目，我们提出肿瘤相关成纤维细胞通过分泌外泌体miR-146a-5p促进膀胱癌干性维持。结果上，我们首先在体内和体外实验中确认了肿瘤相关成纤维细胞对膀胱癌的干性维持作用是通过外泌体介导；其次，我们通过实验验证了外泌体miR-146a-5p对膀胱癌干性维持的具有促进作用；再者，发现miR-146a-5p的下游靶基因和信号通路是ARID1A和AMPKα2；最后，拮抗miR-146a具有抗膀胱癌作用，病人血液中外泌体miR-146a-5p的表达与膀胱癌预后相关。本研究揭示了肿瘤相关成纤维细胞外泌体miR-146a-5p通过靶向ARID1A和AMPKα2信号通路介导膀胱癌干性维持的分子机理，外泌体miR-146a-5p是膀胱癌治疗的潜在药物靶点。