title: Overexpression of endothelin 1 triggers hepatocarcinogenesis in zebrafish and promotes cell proliferation and migration through the AKT pathway.
abstract: 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.
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan ; Department of Life Sciences, National Central University, Jhongli City, Taoyuan, Taiwan.
authors.forename: Jeng-Wei
authors.initials: JW
authors.lastname: Lu
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan ; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chung-Yi
authors.initials: CY
authors.lastname: Liao
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors.forename: Wan-Yu
authors.initials: WY
authors.lastname: Yang
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua City, Changhua County, Taiwan ; Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
authors.forename: Yueh-Min
authors.initials: YM
authors.lastname: Lin
authors.affiliation: Department of Life Sciences, National Central University, Jhongli City, Taoyuan, Taiwan.
authors.forename: Shiow-Lian Catherine
authors.initials: SL
authors.lastname: Jin
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Horng-Dar
authors.initials: HD
authors.lastname: Wang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan ; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan ; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Chiou-Hwa
authors.initials: CH
authors.lastname: Yuh
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005234:Fatty Liver / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D029961:Zebrafish Proteins; C000589536:Mirn1 microRNA, zebrafish; C414282:edn1 protein, zebrafish