Xiu-Yan Huang1, Zi-Li Huang2, Jin Huang3, Bin Xu4, Xin-Yu Huang5, Yong-Hua Xu2, Jian Zhou6, Zhao-You Tang6. 1. Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai, 200233, People's Republic of China. xyhuang1119@163.com. 2. Department of Radiology, Xuhui District Central Hospital of Zhongshan Hospital, Fudan University, Shanghai, 200031, People's Republic of China. 3. Department of Pathology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China. 4. Department of General Surgery, the Tenth People's Hospital of Tongji University, Shanghai, 200072, People's Republic of China. 5. Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai, 200233, People's Republic of China. 6. Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
Abstract
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.
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 HCCpatients 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 HCCpatients 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.