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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
Rhee, H; Kim, HY; Choi, JH; Woo, HG; Yoo, JE; Nahm, JH; Choi, JS; Park, YN
Citation
Cancer research, 78(7):1619-1631, 2018
Journal Title
Cancer research
ISSN
0008-54721538-7445
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.
MeSH terms
Cancer-Associated Fibroblasts/pathologyCarcinoma, Hepatocellular/mortalityCarcinoma, Hepatocellular/pathology*Cell Line, TumorExtracellular Signal-Regulated MAP Kinases/metabolism*Hep G2 CellsHepatic Stellate Cells/pathologyHepatocyte Growth Factor/metabolism*HumansKeratin-19/metabolism*Liver Neoplasms/mortalityLiver Neoplasms/pathology*MAP Kinase Signaling System/physiologyPrognosisProto-Oncogene Proteins c-fos/metabolism*Proto-Oncogene Proteins c-met/metabolism*Sp1 Transcription Factor/metabolism*Transcription Factor AP-1/metabolism*
DOI
10.1158/0008-5472.CAN-17-0988
PMID
29363547
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
최, 지혜우, 현구
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