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Keratin 19 Expression in Hepatocellular Carcinoma Is Regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis

Authors
 Hyungjin Rhee  ;  Hye-Young Kim  ;  Ji-Hye Choi  ;  Hyun Goo Woo  ;  Jeong Eun Yoo  ;  Ji Hae Nahm  ;  Jin-Sub Choi  ;  Young Nyun Park 
Citation
 Cancer Research, Vol.78(7) : 1619-1631, 2018 
Journal Title
 Cancer Research 
ISSN
 0008-5472 
Issue Date
2018
Abstract
Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC); however, regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that cross-talk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an in vitro model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. HSCs upregulated transcription and translation of KRT19 in HCC cells via paracrine interactions. Mechanistically, hepatocyte growth factor (HGF) from HSCs activated c-MET and the MEK-ERK1/2 pathway, which upregulated KRT19 expression in HCC cells. Furthermore, AP1 (JUN/FOSL1) and SP1, downstream transcriptional activators of ERK1/2, activated KRT19 expression in HCC cells. In clinical specimens of human HCC (n = 339), HGF and KRT19 protein expression correlated with CAF levels. In addition, HGF or MET protein expression was associated with FOSL1 and KRT19 expression and was found to be a poor prognostic factor. Analysis of data from The Cancer Genome Atlas also revealed KRT19 expression was closely associated with CAF and MET-mediated signaling activities. These results provide insights into the molecular background of KRT19-positive HCC that display an aggressive phenotype.Significance: These findings reveal KRT19 expression in hepatocellular carcinoma is regulated by cross-talk between cancer-associated fibroblasts and HCC cells, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(7); 1619-31. (c)2018 AACR.
Full Text
http://cancerres.aacrjournals.org/content/78/7/1619
DOI
10.1158/0008-5472.can-17-0988
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
남지해(Nahm, Ji Hae) ORCID logo https://orcid.org/0000-0003-0902-866X
박영년(Park, Young Nyun) ORCID logo https://orcid.org/0000-0003-0357-7967
유정은(Yoo, Jeong Eun)
이형진(Rhee, Hyungjin) ORCID logo https://orcid.org/0000-0001-7759-4458
최진섭(Choi, Jin Sub)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/162133
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