Exosome介导miR-210转运促进肾细胞癌肺转移的机制研究

For localized Renal cell carcinoma (RCC), about 20%-30% of postoperative patients develop metastatic recurrence. Those patients with metastatic RCC have a very poor prognosis. This has been the biggest problem in RCC treatment, so metastasis research of RCC will have great significance. The newly discovered exosomal miRNA could modulate tumor microenvironment and involve in tumor metastasis, but the mechanism remains poorly understood. On our previous studies, we found different miRNAs profile between RCC and their matched adjacent noncancerous tissues. miR-210, which was significantly up-regulated in RCC tissue, was secreted by tumor cells into blood circulation via exosomes. Especially in RCC patients with lung metastasis, exosomal miR–210 highestly expressed in serum. Base on previous studies, the purpose of this research is to verify exosome-mediated cell-to-cell communication in RCC, and better understand the molecular mechanisms that transfer of exosome-mediated miR-210 into serum can promote the lung metastasis of renal cancer cells. Such research may be conducive to the development of novel target therapy.

局限性肾癌患者手术后仍有20-30%复发成为转移性肾癌，且预后很差。这一直是困扰肾癌治疗的最大问题，因此肾癌转移机制的研究将具有十分重要的研究意义。新近发现了循环exosomal miRNA能够影响肿瘤微环境并参与肿瘤的侵袭转移，但对其具体作用机制解释甚少。我们前期miRNA芯片研究发现肾癌组织miR-210表达明显高于癌旁组织，肾癌患者血清中存在大量exosomal miR-210，尤其是在肺转移患者血清中exosomal miR-210表达最高。基于前期研究，本课题的目地是探讨肾癌细胞分泌exosome介导miR-210通过细胞-细胞间通信，促进肾癌细胞肺部转移，从循环miRNA角度揭示肾癌细胞转移的机制，为发现新的肾癌治疗方法及提高肿瘤治疗效果打下理论基础。

有研究显示外泌体miRNAs能够反映在其起源细胞中发生的分子变化，并且是癌症早期检测的潜在指标。 基于ccRCC miRNA表达谱，我们通过定量PCR分析了它们在组织，血清和血清外泌体中的表达。结果显示只有miR-210在肾癌患者血清和肾癌患者血清外泌体中高表达。血清外泌体miR-210的含量要明显高于提取外泌体后的血清悬浮液，ROC曲线表明血清外泌体miR-210诊断肾透明细胞癌的敏感性和特异性分别可达82.5%和80.0%。外泌体miR-210在分期分级和转移患者的表达明显升高，并且在术后一个月再检测时明显下降。 急性缺氧暴露会在正常和肿瘤RCC细胞系中激活miR-210并上调miR-210释放外泌体，并干扰VMP1 mRNA表达，特别是在转移性ccRCC细胞系中。 总之，源自肿瘤组织的血清外泌体miR-210具有潜在的新型无创生物标志物的作用，可用于ccRCC的检测和预后判断。 另研究显示miR-765作为肿瘤抑制因子，可能通过靶向PLP2清除透明细胞肾细胞癌中的脂质，从而抑制肾癌细胞的增殖和转移。

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