Oncotarget
·
2017
·
IF 5.168
Zhe Cheng,Ling-Ling Dai,Xi Wang,Liu-Qun Jia,Xiao-Gang Jing,Peng-Fei Li,Meng Liu,Huan Wang,Lin An
This study aims to explore how microRNA-145 (miR-145) affects airway remodeling and cytokine expression by targeting epidermal growth factor receptor (EGFR) to regulate mucin 5AC (MUC5AC). Mice alveolar epithelial cells (AECs) were divided into a control, blank, miR-145 mimics, mimic control, miR-145 inhibitors, inhibitor control, si- EGFR and miR-145 inhibitors + si- EGFR group. Asthma mice models with airway remodeling were induced with an Ovalbumin (OVA) solution and randomly divided into a normal, asthma, asthma + miR-145 mimics, asthma + miR-145 mimic control, asthma + si- EGFR or asthma + si- EGFR NC group. Airway remodeling degree and histomorphology was measured using hematoxylin-eosin (HE), Masson and periodic acid-Schiff (PAS) staining. Flow cytometry was used to detect Th2 and Th17 cells in peripheral blood, ELISA was used to measure inflammatory factors. qRT-PCR and western blotting was adapted to detect the expressions of EGFR and the relevant cytokines that are regulated by miR-145. The control, miR-145 mimics and si- EGFR groups showed a higher expression of miR-145 and a lower expression of EGFR and cytokines than the blank, mimic control, inhibitor control and miR-145 inhibitor + si- EGFR groups. Mice in the asthma + miR-145 mimics and asthma + si- EGFR groups showed lower WAt/Pbm, WAi/Pbm and WAm/Pbm, less inflammatory cells, less airway modeling and alleviated goblet cell hyperplasia and mucus obstruction than the asthma group. Furthermore, the expressions of EGFR and cytokines of transfected cells and lung tissues were negatively related to those of miR-145. MiR-145 can down-regulate MUC5AC by negatively targeting EGFR and thereby relieving airway remodeling.
研究领域:
分子生物学
·
呼吸医学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2018
·
IF 3.831
Yang Junfa,Liu Qingxue,Cao Shiyang,Xu Tao,Li Xiaofeng,Zhou Dandan,Pan Linxin,Li Changyao,Huang Cheng,Meng Xiaoming,Zhang Lei,Wang Xiao
During the liver fibrosis recovery stage tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can effectively induce apoptosis of activated hepatic stellate cells (HSCs). Normal hepatic stellate cells are resistant to TRAIL cytotoxicity. Therefore, enhancing the sensitivity of TRAIL-induced apoptosis of HSCs may be useful to treat hepatic fibrogenesis. Here, we demonstrated that miR-145 and TRAIL were down-regulated in both liver fibrosis tissue samples and transforming growth factor-β1 induced HSCs, concomitant with increased the expression of ZEB2. In addition, we found that mimics-mediated over-expression of miR-145 led to resistance to the ZEB2 expression and up-regulation of the TRAIL-induced apoptosis after treatment of LX-2 cells with TRAIL. Furthermore, ZEB2-siRNA transfected LX-2 cells showed the increased sensitivity to TRAIL-induced apoptosis. Whereas, opposite results were obtained in miR-145-inhibitor group or ZEB2 plasmid group. Moreover, miR-145 regulated ZEB2 gene expression by specifically interacting with the 3′-UTR of ZEB2 mRNA to inhibit the expression of ZEB2. Further studies showed that the over-expression of ZEB2 could inhibit TRAIL-induced apoptosis via inhibiting nuclear factor-κB (NF-κB) signaling pathway in LX-2 cells. Collectively, our data suggest that up-regulation of miR-145 can down-regulate ZEB2 expression, consequently promoting TRAIL-induced apoptosis in LX-2 cells through NF-κB signaling pathway, which facilitates the resolution of liver fibrosis.
研究领域:
分子生物学
·
细胞生物学
·
肝病学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2018
·Vol. 234
·期 5
·7587-7599
·
IF 3.923
Junfa Yang,Yuchen Lu,Peipei Yang,Qingfeng Chen,Yang Wang,Qi Ding,Tao Xu,Xiaofeng Li,Changyao Li,Cheng Huang,Xiaoming Meng,Jun Li,Lei Zhang,Xiao Wang
Activation of quiescent hepatic stellate cells (HSCs) is the major event in liver fibrosis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. The p53, a guardian of the genome is associated with liver fibrosis, has been shown to regulate HSCs senescence. In this study, we report that microRNA-145 (miR-145) and p53 were downregulated in vivo and in vitro, concomitant with the enhanced expression of zinc finger E-box binding homeobox 2 (ZEB2). In addition, overexpression of miR-145 and p53 led to upregulation of the number of senescence-associated β-galactosidase-positive HSCs and the expression of senescence markers p16 and p21, along with the reduced abundance of HSC activation markers α-smooth muscle actin and type I collagen in activated HSCs. Furthermore, silencing of ZEB2 promoted senescence of activated HSCs. Moreover, we also demonstrated that miR-145 specifically targeted the 3′-untranslated regions of ZEB2. In vitro promoter regulation studies show that ZEB2 could bind to the E-box of the p53 promoter as well as inhibit its promoter activity and thus suppress the expression of p53, which in turn repressed activated HSCs senescence. Taken together, our results describe a novel miR-145-ZEB2-p53 regulatory line might participate in the senescence of activated HSCs and might carry potential therapeutic targets for restraining liver fibrosis.
研究领域:
分子生物学
·
细胞生物学
·
肝病学
✓ 已验证
DOI
PubMed
高影响因子
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