Involvement of ERK1/2 activation in the gene expression of senescence-associated secretory factors in human hepatic stellate cells

Abstract

Senescent hepatic stellate cells (senescent HSCs) are found in patients with liver cirrhosis and have been thought to be involved in the development of hepatocellular carcinoma (HCC) in mice via the senescence-associated secretory proteins. However, in humans, which secretory proteins are involved and what regulate their expression remain unclear. In the current study, we characterized senescence-associated β-galactosidase-positive senescent human HSCs (hHSCs) induced by repetitive passaging. They exhibited enhanced expression of 14 genes for secretory protein and persistent phosphorylation of ERK1/2 protein but not JNK or p38 MAPK proteins. Enhanced nuclear ERK1/2 phosphorylation was observed in senescent hHSCs. Treatment of the senescent hHSCs with ERK1/2 inhibitor, SCH772984, significantly decreased the levels of angiopoietin like 4 (ANGPTL4), CC motif chemokine ligand 7 (CCL7), Interleukin-8 (IL-8), platelet factor 4 variant 1 (PF4V1), and TNF superfamily member 15 (TNFSF15) mRNA levels in a dose-dependent manner. The enhanced phosphorylation of ERK1/2 and expression of ANGPTL4, IL-8 and PF4V1 genes were observed in both of senescent human dermal fibroblasts and X-ray-induced senescent hHSCs. However, transient ERK1/2 activation induced by epidermal growth factor could not mimic the gene profile of the senescent hHSCs. These results revealed involvement of ERK1/2 signalling in the regulation of senescence-associated secretory factors, suggesting that simultaneous induction of ANGPTL4, IL-8, and PF4V1 genes is a marker 3 of hHSC senescence. This study will contribute to understanding roles of senescent hHSCs in liver diseases.

Functional Roles of Chemokine Receptor CCR2 and Its Ligands in Liver Disease

“…The chromatin remodeling protein Brahma-related gene 1 (BRG1) interacts with activator protein 1 (AP-1) to activate the transcription of CCL7, which in turn promotes macrophage accumulation in the liver (25). In addition, microarray analysis showed that consecutive ERK1/2 activation induces the expression of senescence related secretory factors including CCL7, indicating that CCL7 can be used as a marker of human HSC senescence (26). In the liver tumor microenvironment, there is a group of specialized fibroblasts that are defined as cancer-associated fibroblasts (CAFs) (88,89).…”

Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells

“…The ERK1/2 signaling pathway is considered to have great effects on proliferation, invasion, and migration in cancer cells. Numerous studies have confirmed that ERK1/2 signaling is the main regulator that promotes the progression of human hepatocellular carcinoma ( 30 – 34 ). ERK1/2 participates in liver injury in human liver stem cells ( 35 , 36 ).…”

Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells

“…The ERK1/2 signalling pathway was considered to have great effects on proliferation, invasion and migration in cancer cells. Numerous researches have con rmed that ERK1/2 signalling might be a main regulator to promote the progression of human hepatocellular carcinoma (26)(27)(28)(29)(30). The ERK1/2 participated in liver injury in human liver stem cells (31,32).…”