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

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 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. .

Activation of extracellular signal‐regulated kinase is associated with hepatocellular carcinoma with aggressive phenotypes

“…Therefore, the present findings suggest that KRT19‐positive HCC cases might be conditioned by the involvement of the HGF/c‐MET/ERK axis, in addition to the innate KRT19 expression in HCCs. A recent study showed that KRT19 expression in HCC was regulated by the cancer‐associated fibroblast‐derived HGF through the c‐MET/ERK/AP1 and SP1 axis, which is consistent with the present findings . These findings might indicate that the HGF/c‐MET/ERK axis is partly involved in the development of KRT19‐expressing HCC.…”

“…A recent study showed that KRT19 expression in HCC was regulated by the cancer-associated fibroblast-derived HGF through the c-MET/ERK/AP1 and SP1 axis, which is consistent with the present findings. 57 These findings might indicate that the HGF/c-MET/ERK axis is partly involved in the development of KRT19-expressing HCC.…”

The Efficacy of Various Machine Learning Models for Multi-class Classification of RNA-Seq Expression Data

“…These 20 genes were extracted and displayed in Table 3. Defensin Beta, Interferon, and Keratin Associated Proteins are known to be strong cancer driver genes [25,26]. Actin and Ribonuclease has been shown to play a significant role in some cancer types [27].…”

Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation

“…HGF is highly expressed by activated HSCs and involved in promoting HCC proliferation by binding to its receptor c-Met and activating its downstream ERK1/2 signaling [38][39][40][41][42]. In addition, activation of c-Met/ERK pathway can modulate autophagy processes [43,44].…”