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

doi:10.1016/j.isci.2024.108955

Exosomal miR-3174 induced by hypoxia promotes angiogenesis and metastasis of hepatocellular carcinoma by inhibiting HIPK3

iScience. 2024 Jan 19;27(2):108955. doi: 10.1016/j.isci.2024.108955. eCollection 2024 Feb 16.

Authors

Xiao Yang^{1

2}, Mingyu Wu¹, Xiangxu Kong², Yun Wang³, Chunyang Hu², Deming Zhu⁴, Lianbao Kong^{4

2}, Fei Qiu⁵, Wangjie Jiang^{4

2}

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
⁵ Department of Anesthesiology, The Second Hospital of Nanjing, Nanjing, Jiangsu 210000, China.

Abstract

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.

Keywords: Cancer; Cell biology; Molecular biology.