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FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4-GSK3β-Nrf2 Signaling

The tumor microenvironment induces endoplasmic reticulum (ER) stress in tumor cells, an event that can promote progression, but it is unknown how tumor cells adapt to this stress. In this study, we show that the fibroblast growth factor FGF19, a gene frequently amplified in hepatocellular carcinoma...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2017-11, Vol.77 (22), p.6215-6225
Main Authors: Teng, Yong, Zhao, Huakan, Gao, Lixia, Zhang, Wenfa, Shull, Austin Y, Shay, Chloe
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container_issue 22
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creator Teng, Yong
Zhao, Huakan
Gao, Lixia
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Shull, Austin Y
Shay, Chloe
description The tumor microenvironment induces endoplasmic reticulum (ER) stress in tumor cells, an event that can promote progression, but it is unknown how tumor cells adapt to this stress. In this study, we show that the fibroblast growth factor FGF19, a gene frequently amplified in hepatocellular carcinoma (HCC), facilitates a survival response to ER stress. Levels of FGF19 expression were increased in stressed HCC cells in culture and in a mouse xenograft model. Induction of ER stress required the transcription factor ATF4, which directly bound the FGF19 promoter. In cells where ER stress was induced, FGF19 overexpression promoted HCC cell survival and increased resistance to apoptosis, whereas FGF19 silencing counteracted these effects. Mechanistic investigations implicated glycogen synthase kinase-3β (GSK3β) in regulating nuclear accumulation of the stress-regulated transcription factor Nrf2 activated by FGF19. Our findings show how FGF19 provides a cytoprotective role against ER stress by activating a FGFR4-GSK3β-Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management. .
doi_str_mv 10.1158/0008-5472.CAN-17-2039
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In this study, we show that the fibroblast growth factor FGF19, a gene frequently amplified in hepatocellular carcinoma (HCC), facilitates a survival response to ER stress. Levels of FGF19 expression were increased in stressed HCC cells in culture and in a mouse xenograft model. Induction of ER stress required the transcription factor ATF4, which directly bound the FGF19 promoter. In cells where ER stress was induced, FGF19 overexpression promoted HCC cell survival and increased resistance to apoptosis, whereas FGF19 silencing counteracted these effects. Mechanistic investigations implicated glycogen synthase kinase-3β (GSK3β) in regulating nuclear accumulation of the stress-regulated transcription factor Nrf2 activated by FGF19. 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subjects Activating transcription factor 4
Animals
Apoptosis
Blotting, Western
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Cell culture
Cell Line
Cell Line, Tumor
Cell survival
Endoplasmic reticulum
Endoplasmic Reticulum Stress
Fibroblast growth factor receptor 4
Fibroblast Growth Factors - genetics
Fibroblast Growth Factors - metabolism
Fibroblasts
Gene Expression Regulation, Neoplastic
Glycogen
Glycogen synthase kinase 3
Glycogen Synthase Kinase 3 beta - metabolism
Growth factors
Hep G2 Cells
Hepatocellular carcinoma
Humans
Kinases
Liver
Liver cancer
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Mice, Inbred BALB C
Mice, Nude
NF-E2-Related Factor 2 - metabolism
Receptor, Fibroblast Growth Factor, Type 4 - genetics
Receptor, Fibroblast Growth Factor, Type 4 - metabolism
Signal Transduction
Stress
Transcription factors
Transplantation, Heterologous
Tumor cells
Xenografts
title FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4-GSK3β-Nrf2 Signaling
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