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

被引：10

作者：

Odagiri, Naoshi ^{[1
,2
]}

Matsubara, Tsutomu ^{[1
]}

Higuchi, Moe ^{[1
]}

Takada, Sayuri ^{[1
,2
]}

Urushima, Hayato ^{[1
]}

Sato-Matsubara, Misako ^{[2
,3
]}

Teranishi, Yuga ^{[2
]}

Yoshizato, Katsutoshi ^{[3
,4
]}

Kawada, Norifumi ^{[2
]}

Ikeda, Kazuo ^{[1
]}

机构：

[1] Osaka City Univ, Grad Sch Med, Dept Anat & Regenerat Biol, Osaka 5458585, Japan

[2] Osaka City Univ, Grad Sch Med, Dept Hepatol, Osaka 5458585, Japan

[3] Osaka City Univ, Grad Sch Med, Endowed Lab Synthet Biol, Osaka 5458585, Japan

[4] PhoenixBio Co Ltd, Acad Advisors Off, Higashihiroshima 7390046, Japan

来源：

MOLECULAR AND CELLULAR BIOCHEMISTRY | 2019年 / 455卷 / 1-2期

关键词：

Hepatic stellate cell; Senescence; Secretory factor; ERK1; 2; Fibroblast; CELLULAR SENESCENCE; CANCER; FIBROBLASTS; GROWTH; INTERLEUKIN-8; ANGIOGENESIS; PHENOTYPE; INVASION;

D O I：

10.1007/s11010-018-3466-x

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 -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), C-C 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 signaling in the regulation of senescence-associated secretory factors, suggesting that simultaneous induction of ANGPTL4, IL-8, and PF4V1 genes is a marker of hHSC senescence. This study will contribute to understanding roles of senescent hHSCs in liver diseases.

引用

页码：7 / 19

页数：13