Overexpression of endothelin 1 triggers hepatocarcinogenesis in zebrafish and promotes cell proliferation and migration through the AKT pathway

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題名:	Overexpression of endothelin 1 triggers hepatocarcinogenesis in zebrafish and promotes cell proliferation and migration through the AKT pathway
作者:	金秀蓮;Lu, Jeng-Wei;Liao, Chung-Yi;Yang, Wan-Yu;Lin, Yueh-Min;Jin, Shiow-Lian Catherine;Wang, Horng-Dar;Yuh, Chiou-Hwa
貢獻者:	生醫理工學院生命科學系
關鍵詞:	1-Phosphatidylinositol 3-kinase;AKT protein;Animal genetic engineering;Animals;Bile ducts;Biology;Carcinoma, Hepatocellular - etiology;Carcinoma, Hepatocellular - genetics;Carcinoma, Hepatocellular - metabolism;Carcinoma, Hepatocellular - pathology;Cell culture;Cell Cycle;Cell growth;Cell migration;Cell Movement;Cell Proliferation;Cirrhosis;Danio rerio;Endothelin;Endothelin 1;Endothelin-1 - antagonists & inhibitors;Endothelin-1 - genetics;Endothelin-1 - metabolism;Endothelins;Fatty Liver - complications;Fatty Liver - genetics;Fatty Liver - metabolism;Fatty Liver - pathology;Fibrosis;Gene Expression;Genes;Genetically modified animals;Glycogen;HEK293 Cells;Hepatitis;Hepatocellular carcinoma;Hepatocytes;Humans;Hyperplasia;Inhibitors;Liver;Liver cancer;Liver cirrhosis;Liver Cirrhosis - complications;Liver Cirrhosis - genetics;Liver Cirrhosis - metabolism;Liver Cirrhosis - pathology;Liver Neoplasms - etiology;Liver Neoplasms - genetics;Liver Neoplasms - metabolism;Liver Neoplasms - pathology;Medicine;MicroRNAs - genetics;MicroRNAs - metabolism;Phosphatidylinositol 3-Kinases - antagonists & inhibitors;Phosphatidylinositol 3-Kinases - genetics;Phosphatidylinositol 3-Kinases - metabolism;Protein folding;Protein Kinase Inhibitors - pharmacology;Proto-Oncogene Proteins c-akt - antagonists & inhibitors;Proto-Oncogene Proteins c-akt - genetics;Proto-Oncogene Proteins c-akt - metabolism;Ribonucleic acid;RNA;Rodents;Steatosis;T cells;Transgenic fish;Unfolded Protein Response - genetics;Xenografts;Xenotransplantation;Zebrafish;Zebrafish Proteins - antagonists & inhibitors;Zebrafish Proteins - genetics;Zebrafish Proteins - metabolism
日期:	2014-01-08
上傳時間:	2026-04-23 11:13:34 (UTC+8)
出版者:	Public Library of Science;United States: Public Library of Science (PLoS)
摘要:	摘要： Hepatocarcinogenesis commonly involves the gradual progression from hepatitis to fibrosis and cirrhosis, and ultimately to hepatocellular carcinoma (HCC). Endothelin 1 (Edn1) has been identified as a gene that is significantly up-regulated in HBx-induced HCC in mice. In this study, we further investigated the role of edn1 in hepatocarcinogenesis using a transgenic zebrafish model and a cell culture system. Liver-specific edn1 expression caused steatosis, fibrosis, glycogen accumulation, bile duct dilation, hyperplasia, and HCC in zebrafish. Overexpression of EDN1 in 293T cells enhanced cell proliferation and cell migration in in vitro and xenotransplantation assays and was accompanied with up-regulation of several cell cycle/proliferation- and migration-specific genes. Furthermore, expression of the unfolded protein response (UPR) pathway-related mediators, such as spliced XBP1, ATF6, IRE1, and PERK, was also up-regulated at both the RNA and protein levels. In the presence of an EDN1 inhibitor or an AKT inhibitor, these increases were diminished and the EDN1-induced migration ability also was disappeared, suggesting that the EDN1 effects act through activation of the AKT pathway to enhance the UPR and subsequently activate the expression of downstream genes. Additionally, p-AKT is enhanced in the edn1 transgenic fish compared to the GFP-mCherry control. The micro RNA miR-1 was found to inhibit the expression of EDN1. We also observed an inverse correlation between EDN1 and miR-1 expression in HCC patients. In conclusion, our data suggest that EDN1 plays an important role in HCC progression by activating the PI3K/AKT pathway and is regulated by miR-1. 其他題名： PLoS One 出版者： United States: Public Library of Science (PLoS) 出版日期： 2014-01-08 出處： PLoS ONE, 2014-01, Vol.9 (1), p.e85318- 資源來源： Agricultural & Environmental Science Collection 版權： COPYRIGHT 2014 Public Library of Science 版權： 2014 Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 版權： 2014 Lu et al 2014 Lu et al 識別號： ISSN: 1932-6203 識別號： EISSN: 1932-6203 識別號： DOI: 10.1371/journal.pone.0085318 識別號： PMID: 24416389
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