肿瘤相关成纤维细胞通过外泌体miRNA调控肾细胞癌干性的机制研究

Recent studies have demonstrated that cancer stemness is the key to tumor recurrence, metastasis and drug resistance, and that cancer-associated fibroblasts (CAFs) play the pivotal role in sustaining cancer stemness. However, the specific biology functions and mechanism of CAFs in renal cell carcinoma (RCC) remain unclear. Our newly studies found that the enrichment of CAFs in RCC tissues was significantly correlated with the progression, prognosis and stemness of RCC. Further investigation revealed that exosome secreted by CAFs could stimulate the proliferation, migration and cancer stemness of RCC cells, specifically, exosomal miRNAs from CAFs maight serve as important regulators. Therefore, we hypothesize that CAFs could secret exosomal miRNAs to RCC cells, sustaining cancer stemness, thus promoting the growth and metastasis of RCC. In order to verify this hypothesis, we will adopt clinical samples, cell lines, and tumor-xenograft mouse model to explore the role and mechanism of CAFs and their exosomal miRNAs in cancer stemness and metastasis of RCC, and further evaluate the clinical value of CAFs exosomal miRNAs in the treatment of RCC. The purpose of our study is to provide new ideas and new ways for elucidating the molecular mechanism and developing more effective treatment strategies of RCC.

最新研究发现，肿瘤干性是恶性肿瘤复发、转移和耐药的关键所在，肿瘤相关成纤维细胞（CAF）在肿瘤干性调控中发挥重要作用。然而，在肾细胞癌（RCC）中，CAF的具体功能和机制尚不清晰。我们前期研究发现，临床RCC组织中CAF的富集与RCC的进展、预后和干性明显相关； 进一步探究发现，CAF分泌的exosome可影响RCC细胞的增殖、迁移和干性等功能，且其中的关键exosomal miRNA是重要的调控因子。据此提出假说：在肾癌中，CAF可通过分泌exosomal miRNA调控肿瘤干性，介导RCC的生长和转移。为验证假说，我们拟通过临床标本、细胞及动物研究，探索肿瘤微环境中CAF及其分泌的exosomal miRNA在RCC干性维持和转移中的功能及机制，并评估其在RCC治疗中的临床价值，为阐明RCC发生发展的分子机制，制定更有效的治疗策略提供新思路和新途径。

肿瘤相关成纤维细胞(CAF)在肾细胞癌(RCC)干性和肿瘤进展中的功能和调控机制不明。在本研究中，我们发现RCC组织中CAF的富集与肿瘤进展和肿瘤干性显著正相关。进一步的研究表明，CAF可通过分泌外泌体增强肿瘤细胞干性，介导肿瘤进展；随后通过对NF和CAF细胞外泌体小RNA测序和筛选，发现miR-181d-5p是CAF外泌体中的关键调控因子。在分子机制方面，CAF分泌外泌体miR-181d-5p到RCC细胞中，直接抑制Wnt/β-catenin通路抑制因子RNF43的表达，激活Wnt/β-catenin信号通路，从而增强肿瘤干性，介导肿瘤进展。综上，本研究结果揭示了CAF外泌体miRNA调控肿瘤干性促进RCC进展的关键分子机制，提出了一种基于CAF外泌体miRNA的有潜力的RCC临床治疗新途径。