BACKGROUND Exosomes play crucial roles in regulating the crosstalk between normal and cancer cells in the tumor microenvironment, and in regulating cancer proliferation, migration and invasion through their cargo molecules. METHODS We analyzed the pro-invasiveness of exosomal circRNA-100,338 in HCC using the transwell invasion assay. The co-culture of human umbilical vein endothelial cells (HUVEC) and exosomes derived from HCC cell lines were used to evaluate the impact of HCC derived exosomes on HUVEC. Nude mice models were used to validate the findings in vitro. Clinically, quantitative RT-PCR was used to quantify the expression of serum exosomal circRNA-100,338 in HCC patients at both pre-surgery within one week and post-surgery within three weeks. RESULTS We aim to investigate the pro-invasive role of exosomal circRNA-100,338 in HCC metastasis. We for the first time demonstrated that circRNA-100,338 was highly expressed in both highly metastatic HCC cells and their secreted exosomes. The transwell invasion assay showed that the overexpression or knockdown of exosomal circRNA-100,338 significantly enhanced or reduced the invasive abilities of HCC cells. Subsequently, in vitro and in vivo assays showed that exosomal circRNA-100,338 affected the cell proliferation, angiogenesis, permeability, and vasculogenic mimicry (VM) formation ability of human umbilical vein endothelial cells (HUVEC), and tumor metastasis. Furthermore, we also observed that the persistent high expression of exosomal circRNA-100,338 in serum of HCC patients who underwent curative hepatectomy may be a risk indicator of pulmonary metastasis and poor survival. CONCLUSIONS Our findings indicated that metastatic ability of HCC cells could be enhanced by transferring exosomal circRNA-100,338 to recipient HUVECs, which could affect proangiogenic activity by regulating angiogenesis.

中文翻译：

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外体circRNA-100338通过增强侵袭性和血管生成促进肝细胞癌转移。

背景技术外来体在调节肿瘤微环境中正常细胞与癌细胞之间的串扰以及调节通过其货物分子的癌症增殖，迁移和侵袭中起关键作用。方法我们使用transwell入侵分析法分析了外体circRNA-100,338在肝癌中的侵袭性。使用人脐静脉内皮细胞（HUVEC）和源自HCC细胞系的外泌体的共培养物来评估HCC来源的外泌体对HUVEC的影响。使用裸鼠模型在体外验证发现。临床上，定量RT-PCR用于量化术前一周内和术后三周内HCC患者血清外泌体circRNA-100,338的表达。结果我们旨在研究外泌体circRNA-100的促侵袭作用，338例发生HCC转移。我们首次证明，circRNA-100,338在高度转移的HCC细胞及其分泌的外泌体中均高表达。Transwell侵袭试验表明，exosomal circRNA-100,338的过表达或敲低显着增强或降低了HCC细胞的侵袭能力。随后，体外和体内试验表明，外泌体circRNA-100,338影响人脐静脉内皮细胞（HUVEC）的细胞增殖，血管生成，通透性和血管生成模拟物（VM）的形成能力，以及肿瘤转移。此外，我们还观察到接受根治性肝切除的HCC患者血清中外泌体circRNA-100,338的持续高表达可能是肺转移和生存不良的危险指标。