Exosomal miR-3174 induced by hypoxia promotes angiogenesis and metastasis of hepatocellular carcinoma by inhibiting HIPK3
Xiao Yang,
Mingyu Wu,
Xiangxu Kong,
Yun Wang,
Chunyang Hu,
Deming Zhu,
Lianbao Kong,
Fei Qiu,
Wangjie Jiang
Affiliations
Xiao Yang
Department of Hepatobiliary Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu 214023, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu 210000, China
Mingyu Wu
Department of Hepatobiliary Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu 214023, China
Xiangxu Kong
Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu 210000, China
Yun Wang
Department of Hepatobiliary Surgery, Xuzhou City Central Hospital, The Affiliated Hospital of the Southeast University Medical School (Xu zhou), The Tumor Research Institute of the Southeast University (Xu zhou), Xuzhou clinical college of Xuzhou Medical University, 199 Jiefang South Road, Xuzhou, Jiangsu 221009, China
Chunyang Hu
Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu 210000, China
Deming Zhu
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China
Lianbao Kong
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu 210000, China; Corresponding author
Fei Qiu
Department of Anesthesiology, The Second Hospital of Nanjing, Nanjing, Jiangsu 210000, China; Corresponding author
Wangjie Jiang
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu 210000, China; Corresponding author
Summary: Hepatocellular carcinoma (HCC) is a highly malignant tumor with rich blood supply. HCC-derived exosomes containing hereditary substances including microRNAs (miRNAs) were involved in regulating tumor angiogenesis and metastasis. Subsequently, series experiments were performed to evaluate the effect of exosomal miR-3174 on HCC angiogenesis and metastasis. HCC-derived exosomal miR-3174 was ingested by human umbilical vein endothelial cells (HUVECs) in which HIPK3 was targeted and silenced, causing subsequent inhibition of Fas and p53 signaling pathways. Furthermore, exosomal miR-3174 induced permeability and angiogenesis of HUVECs to enhance HCC progression and metastasis. Under hypoxia, upregulated HIF-1α further promoted the transcription of miR-3174. Moreover, HNRNPA1 augmented the package of miR-3174 into exosomes. Clinical data analysis confirmed that HCC patients with high-level miR-3174 were correlated with worse prognosis. Thus, exosomal miR-3174 induced by hypoxia promotes angiogenesis and metastasis of HCC by inhibiting HIPK3/p53 and HIPK3/Fas signaling pathways. Our findings might provide potential targets for anti-tumor therapy.
