Ribose-5-phosphate isomerase A overexpression promotes liver cancer development in transgenic zebrafish via activation of ERK and β-catenin pathways
| Autor: | Li-Yang Chen, Hsiao-Chen Tu, Yu-Ting Chou, Chiou-Hwa Yuh, Jeng-Wei Lu, Horng-Dar Wang, Shih-Ci Ciou, Shin-Lin Tsai |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research Carcinogenesis medicine.disease_cause Animals Genetically Modified 03 medical and health sciences Liver Neoplasms Experimental 0302 clinical medicine Cell Line Tumor medicine Animals Extracellular Signal-Regulated MAP Kinases Zebrafish Aldose-Ketose Isomerases beta Catenin biology Chemistry Kinase General Medicine biology.organism_classification Cell biology 030104 developmental biology Ribose-5-phosphate isomerase 030220 oncology & carcinogenesis Catenin Disease Progression Signal transduction Transaldolase |
| Zdroj: | Carcinogenesis |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgy155 |
| Popis: | Dysregulation of the enzymes involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. Our recent study demonstrated that ribose-5-phosphate isomerase (RPIA), a key regulator of the PPP, regulates hepatoma cell proliferation and colony formation. Our studies in zebrafish reveal that RPIA-mediated hepatocarcinogenesis requires extracellular signal-regulated kinase (ERK) and β-catenin signaling. To further investigate RPIA-mediated hepatocarcinogenesis, two independent lines of transgenic zebrafish expressing human RPIA in the liver were generated. These studies reveal that RPIA overexpression triggers lipogenic factor/enzyme expression, steatosis, fibrosis and proliferation of the liver. In addition, the severity of fibrosis and the extent of proliferation are positively correlated with RPIA expression levels. Furthermore, RPIA-mediated induction of hepatocellular carcinoma (HCC) requires the ERK and β-catenin signaling pathway but is not dependent upon transaldolase levels. Our study presents a mechanism for RPIA-mediated hepatocarcinogenesis and suggests that RPIA represents a valuable therapeutic target for the treatment of HCC. Using a transgenic zebrafish model, we found overexpression RPIA in the liver facilitate the steatosis at 5-months, fibrosis at 7-month, and promote hyperplasia or hepatocellular carcinoma (HCC) at 9 and 11 months. We discovered p-ERK was elevated as early as 5-months, and β-catenin signaling pathway were activated from 7-months revealed by IHC. Using oral gavage to treat 7-months RPIA transgenic fish with the inhibitors for one month, we found blockade ERK pathway diminished the expression of lipogenic factor, while β-catenin inhibitor reverted the upregulation of cell cycle/proliferation markers mediated by RPIA overexpression. The combination of β-catenin and ERK inhibitors synergistically reduced the RPIA-induced cellular proliferation in xenotransplantation assay. Our data suggested activation of ERK pathway induce lipogenesis while activation of β-catenin pathway promoting cancer formation at later stage, inhibition of ERK and β-catenin signaling can significantly reduce HCC progression. |
| Databáze: | OpenAIRE |
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