DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats

被引：172

作者：

Bian, Er-Bao ^{[1
]}

Huang, Cheng ^{[1
]}

Ma, Tao-Tao ^{[1
]}

Tao, Hui ^{[1
]}

Zhang, Hui ^{[1
]}

Cheng, Chang ^{[1
]}

Lv, Xiong-Wen ^{[1
]}

Li, Jun ^{[1
]}

机构：

[1] Anhui Med Univ, Sch Pharm, Hefei 230032, Anhui Province, Peoples R China

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2012年 / 264卷 / 01期

基金：

美国国家科学基金会;

关键词：

Liver fibrosis; Hepatic stellate cell (HSC); DNA methylation; DNA methyltransferase 1 (DNMT1); Phosphatase and tension homolog deleted on chromosome 10 (PTEN); HUMAN CANCER-CELLS; TGF-BETA; PROMOTER HYPERMETHYLATION; TUMOR-SUPPRESSOR; EPIGENETIC REGULATION; SIGNALING PATHWAYS; DNA METHYLATION; CPG METHYLATION; EXPRESSION; FIBROSIS;

D O I：

10.1016/j.taap.2012.06.022

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

Hepatic stellate cell (HSC) activation is an essential event during liver fibrogenesis. Phosphatase and tension homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is a negative regulator of this process. PTEN promoter hypermethylation is a major epigenetic silencing mechanism in tumors. The present study aimed to investigate whether PTEN promoter methylation was involved in HSC activation and liver fibrosis. Treatment of activated HSCs with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC) decreased aberrant hypermethylation of the PTEN gene promoter and prevented the loss of PTEN expression that occurred during HSC activation. Silencing DNA methyltransferase 1 (DNMT1) gene also decreased the PTEN gene promoter methylation and upregulated the PTEN gene expression in activated HSC-T6 cells. In addition, knockdown of DNMT1 inhibited the activation of both ERK and AKT pathways in HSC-T6 cells. These results suggest that DNMT1-mediated PTEN hypermethylation caused the loss of PTEN expression, followed by the activation of the PI3K/AKT and ERK pathways, resulting in HSC activation. Crown Copyright (c) 2012 Published by Elsevier Inc. All rights reserved.

引用

页码：13 / 22

页数：10

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