Hypoxia induced exosomal circRNA promotes metastasis of Colorectal Cancer via targeting GEF-H1/RhoA axis
Hypoxia induced exosomal circRNA promotes metastasis of Colorectal Cancer via targeting GEF-H1/RhoA axis
复制标题
缺氧诱导的外泌体circRNA通过靶向GEF-H1/RhoA轴促进结直肠癌转移
DOI：
10.7150/thno.44419
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Ba, Yi
中科院分区：
文献类型：
--
作者：
Yang, Haiou;Zhang, Haiyang;Ba, Yi
缺氧是实体瘤的重要特征之一。然而，根据离最近血管的距离，肿瘤内的氧供应通常是不均匀的。低氧癌细胞与相对常氧癌细胞的转移潜能存在差异。但是分子机制仍然知之甚少。方法：筛选结直肠癌患者与正常人血浆外泌体中环状rna的差异表达。超离心分离外泌体，RT-qPCR检测RNA表达。通过高强度成像、伤口愈合实验和跨井室迁移实验检测细胞的迁移能力。结果：Circ-133在结直肠癌患者血浆外泌体中富集，并随着疾病进展而升高。来自缺氧细胞的外泌体circ-133被传递到常氧细胞中，通过作用于miR-133a/GEF-H1/RhoA轴促进癌症转移。同时，动物实验显示，敲低circ-133可抑制肿瘤转移。Circ-133有望成为监测肿瘤进展的新生物标志物，并可能成为新的治疗靶点。结论：缺氧来源的外泌体circ-133通过miR-133a/GEF-H1/RhoA轴转运到正常癌细胞中，促进细胞迁移。本研究揭示了肿瘤内氧异质性促进癌症进展的潜在机制。
Hypoxia is one of the important properties of solid tumor. However, oxygen supply within tumors is generally heterogeneous according to the distance from the nearest blood vessel. The discrepancy of metastatic potential exists between hypoxic cancer cells and relatively normoxic cancer cells. But the molecular mechanism remains poorly understood.Methods: Differential expression of circRNAs in plasma exosomes of CRC patients and normal subjects was performed by screening. Exosomes were isolated by ultra-centrifugation and RNA expressions were determined by RT-qPCR. The migratory capacity of cells was performed by high intension imaging, wound healing assay and transwell chamber migration assay.Results: Circ-133 is enriched in the plasma exosomes of CRC patients and increased with the disease progression. Exosomal circ-133 derived from hypoxic cells delivered into normoxic cells and promoted cancer metastasis by acting on miR-133a/GEF-H1/RhoA axis. Meanwhile, animal experiments revealed that knockdown of circ-133 can inhibit tumor metastasis. Circ-133 is expected to be a new biomarker for monitoring tumor progression and might be a novel therapeutic target.Conclusions: Hypoxia-derived exosomal circ-133 transported into normaxic cancer cells and promoted cell migration via miR-133a/GEF-H1/RhoA axis. This study reveals a potential mechanism for that the intra-tumor heterogeneity of oxygen promote cancer progression.