Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Department of Physiology, Ajou University School of Medicine, Suwon, Korea.
Cancer Res. 2018 Apr 1;78(7):1619-1631. doi: 10.1158/0008-5472.CAN-17-0988. Epub 2018 Jan 23.
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 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 ( = 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. 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. .
角蛋白 19（KRT19）是肝细胞癌（HCC）的预后不良标志物；然而，其表达的调节机制尚不清楚。我们之前报道过 KRT19 阳性 HCC 中存在纤维性肿瘤基质，这表明癌相关成纤维细胞（CAF）与肿瘤上皮细胞之间的串扰可能调节 KRT19 的表达。本研究使用 HCC 细胞系（HepG2、SNU423）与肝星状细胞（HSC）之间旁分泌相互作用的模型对此进行了研究，HSC 是肝肌成纤维细胞的主要来源。HSCs 通过旁分泌相互作用上调 HCC 细胞中 KRT19 的转录和翻译。从机制上讲，来自 HSCs 的肝细胞生长因子（HGF）激活 c-MET 和 MEK-ERK1/2 途径，上调 HCC 细胞中 KRT19 的表达。此外，ERK1/2 的下游转录激活子 AP1（JUN/FOSL1）和 SP1 激活 HCC 细胞中 KRT19 的表达。在人类 HCC 的临床标本中（=339），HGF 和 KRT19 蛋白表达与 CAF 水平相关。此外，HGF 或 MET 蛋白表达与 FOSL1 和 KRT19 表达相关，并且被发现是预后不良的因素。对癌症基因组图谱数据的分析还表明，KRT19 的表达与 CAF 和 MET 介导的信号活性密切相关。这些结果为具有侵袭性表型的 KRT19 阳性 HCC 的分子背景提供了深入的了解。这些发现表明，肝癌中 KRT19 的表达受癌相关成纤维细胞与 HCC 细胞之间的串扰调节，为这种侵袭性疾病揭示了新的治疗靶点。
