DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma
Autor: | Jun-Jie Chen, Bin Zhu, Ying Feng, Jun-Ling Yang, Hua Huang, Wan-Jiang Xue, Wen Yuan Chung, Yi-Lin Hu |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Male Cancer Research Carcinoma Hepatocellular Angiogenesis Down-Regulation Mice Nude Transfection medicine.disease_cause Mice chemistry.chemical_compound Downregulation and upregulation medicine Animals Humans Gene silencing HCC RC254-282 Tube formation DNA methylation Research Liver Neoplasms Neoplasms. Tumors. Oncology. Including cancer and carcinogens Middle Aged miR-378a-3p Vascular endothelial growth factor TRAF1 TNF receptor associated factor Oncology chemistry Cancer research Carcinogenesis Chromatin immunoprecipitation Signal Transduction |
Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-19 (2021) Journal of Experimental & Clinical Cancer Research : CR |
ISSN: | 1756-9966 |
Popis: | Background Angiogenesis 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. Methods qRT-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. Results We 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. Conclusion Our 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. |
Databáze: | OpenAIRE |
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