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

Abstract 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. Meth...

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Autores principales:	Bin Zhu, Jun-Jie Chen, Ying Feng, Jun-Ling Yang, Hua Huang, Wen Yuan Chung, Yi-Lin Hu, Wan-Jiang Xue
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Angiogenesis HCC miR-378a-3p TRAF1 DNA methylation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/92450d8b1f70426281f53b95df652367
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spelling	oai:doaj.org-article:92450d8b1f70426281f53b95df6523672021-11-14T12:15:21ZDNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma10.1186/s13046-021-02110-61756-9966https://doaj.org/article/92450d8b1f70426281f53b95df6523672021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02110-6https://doaj.org/toc/1756-9966Abstract 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.Bin ZhuJun-Jie ChenYing FengJun-Ling YangHua HuangWen Yuan ChungYi-Lin HuWan-Jiang XueBMCarticleAngiogenesisHCCmiR-378a-3pTRAF1DNA methylationNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Angiogenesis HCC miR-378a-3p TRAF1 DNA methylation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Angiogenesis HCC miR-378a-3p TRAF1 DNA methylation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Bin Zhu Jun-Jie Chen Ying Feng Jun-Ling Yang Hua Huang Wen Yuan Chung Yi-Lin Hu Wan-Jiang Xue DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma
description	Abstract 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.
format	article
author	Bin Zhu Jun-Jie Chen Ying Feng Jun-Ling Yang Hua Huang Wen Yuan Chung Yi-Lin Hu Wan-Jiang Xue
author_facet	Bin Zhu Jun-Jie Chen Ying Feng Jun-Ling Yang Hua Huang Wen Yuan Chung Yi-Lin Hu Wan-Jiang Xue
author_sort	Bin Zhu
title	DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma
title_short	DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma
title_full	DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma
title_fullStr	DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma
title_full_unstemmed	DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma
title_sort	dnmt1-induced mir-378a-3p silencing promotes angiogenesis via the nf-κb signaling pathway by targeting traf1 in hepatocellular carcinoma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/92450d8b1f70426281f53b95df652367
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DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma

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