제1저자 이형진(병리학교실/현 영상의학교실, Phy-Sci 의과학과 졸, 지도 박영년 교수)
교신저자 박영년(병리학교실, BK21)
Cancer Res. 2018 Jan 23. pii: canres.0988.2017. doi: 10.1158/0008-5472.CAN-17-0988. [Epub ahead of print]
Keratin 19 expression in hepatocellular carcinoma is regulated by fibroblast-derived HGF via a MET-ERK1/2-AP1 and SP1 axis.
Rhee H1, Kim HY1, Choi JH2, Woo HG2, Yoo JE3, Nahm JH1, Choi JS4, Park YN5.
1Department of Pathology, Yonsei University College of Medicine.2Department of Physiology, Ajou University School of Medicine.3Pathology, Brain Korea 21 Project for Medical Science, Center for Chronic Metabolic Disease, Yonsei University College of Medicine.4Department of Surgery, Yonsei University College of Medicine.5Department of Pathology, Yonsei University College of Medicine firstname.lastname@example.org.
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 crosstalk 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. Further, 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.