title: Matrix metalloproteinase-1 induction by diethyldithiocarbamate is regulated via Akt and ERK/miR222/ETS-1 pathways in hepatic stellate cells.
abstract: Matrix metalloproteinase-1 (MMP-1) plays an important role in fibrolysis by degrading excessively deposited collagen I and III. We previously demonstrated that diethyldithiocarbamate (DDC) up-regulates MMP-1 in hepatic stellate cells via the ERK1/2 and Akt signalling pathways. In the current study, we attempted to further explore the molecular mechanisms involved in the regulation of MMP-1. We treated a co-cultured system that included hepatocytes (C3A) and hepatic stellate cells (LX-2) with DDC. The data revealed that the transcriptional factor ETS-1, which is an important regulator of MMP-1, was up-regulated in LX-2 cells following DDC treatment. Furthermore, the up-regulation of MMP-1 by DDC has been abrogated through employing si-ETS-1 to block expression of ETS-1. We found that DDC significantly inhibited the expression of miR-222 in LX-2 cells. We transfected miR-222 mimic into LX-2 cells and then co-cultured the cells with C3A. The up-regulation of ETS-1 and MMP-1 in LX-2 cells treated with DDC were inhibited after miR-222 mimic transfection. These data indicate that DDC up-regulated MMP-1 in LX-2 cells through the miR-222/ETS-1 pathway. Finally, we treated the co-cultured system with an Akt inhibitor (T3830) and an ERK1/2 inhibitor (U0126). Both T3830 and U0126 blocked the suppression of miR-222 by DDC in LX-2. Collectively, these data indicate that DDC up-regulated MMP-1 in LX-2 cells through the Akt and ERK/miR-222/ETS-1 pathways. Our study provides experimental data that will aid the control of the process of fibrolysis in liver fibrosis prevention and treatment.
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China youhong30@sina.com liu_tianhui@163.com.
authors.forename: Tianhui
authors.initials: T
authors.lastname: Liu
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cong
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Li
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Zhai
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China.
authors.forename: Jidong
authors.initials: J
authors.lastname: Jia
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Disease, Beijing 100050, China youhong30@sina.com liu_tianhui@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: You
mesh_terms: D002460:Cell Line; D004050:Ditiocarb / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C494041:ETS1 protein, human; D035683:MicroRNAs; D050784:Proto-Oncogene Protein c-ets-1; D004050:Ditiocarb; D051057:Proto-Oncogene Proteins c-akt; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: ETS-1; diethyldithiocarbamate; liver fibrosis; matrix metalloproteinase-1; microRNA 222