DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma

Journal of Experimental & Clinical Cancer Research

Yi-Lin Hu¹  Wan-Jiang Xue¹  Ying Feng¹  Bin Zhu²  Wen Yuan Chung³  Hua Huang⁴  Jun-Jie Chen⁵  Jun-Ling Yang⁵ 

[1] Department of General Surgery, Affiliated Hospital of Nantong University, 20 Xisi Street, 226001, Nantong, Jiangsu, China;Department of General Surgery, Affiliated Hospital of Nantong University, 20 Xisi Street, 226001, Nantong, Jiangsu, China;Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, 226001, Nantong, Jiangsu, China;Medical school, Nantong University, 19 Qixiu Road, 226001, Nantong, Jiangsu, China;Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, University of Leicester, Gwendolen Road, LE5 4PW, Leicester, UK;Department of Pathology, Affiliated Hospital of Nantong University, 20 Xisi Street, 226001, Nantong, Jiangsu, China;Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, 226001, Nantong, Jiangsu, China;

关键词: Angiogenesis;    HCC;    miR-378a-3p;    TRAF1;    DNA methylation;   

DOI  :  10.1186/s13046-021-02110-6

来源: Springer

【 摘 要 】

BackgroundAngiogenesis plays an important role in the occurrence, development and metastasis of hepatocellular carcinoma (HCC). According to previous studies, miR-378a participates in tumorigenesis and tumor metastasis, but its exact role in HCC angiogenesis remains poorly understood.MethodsqRT-PCR was used to investigate the expression of miR-378a-3p in HCC tissues and cell lines. The effects of miR-378a-3p on HCC in vitro and in vivo were examined by Cell Counting Kit-8 (CCK-8), Transwell, tube formation and Matrigel plug assays, RNA sequencing, bioinformatics, luciferase reporter, immunofluorescence and chromatin immunoprecipitation (ChIP) assays were used to detect the molecular mechanism by which miR-378a-3p inhibits angiogenesis.ResultsWe confirmed that miR-378a-3p expression was significantly downregulated and associated with higher microvascular density (MVD) in HCC; miR-378a-3p downregulation indicated a short survival time in HCC patients. miR-378a-3p knockdown led to a significant increase in angiogenesis in vitro and in vivo. We found that miR-378a-3p directly targeted TNF receptor associated factor 1 (TRAF1) to attenuate NF-κB signaling, and then downregulated secreted vascular endothelial growth factor. DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of miR-378a-3p was responsible for downregulating miR-378a-3p. Moreover, a series of investigations indicated that p65 initiated a positive feedback loop that could upregulate DNMT1 to promote hypermethylation of the miR-378a-3p promoter.ConclusionOur study indicates a novel DNMT1/miR-378a-3p/TRAF1/NF-κB positive feedback loop in HCC cells, which may become a potential therapeutic target for HCC.

【 授权许可】

CC BY