Shuang Ren1,2, Jiamei Chen1, Qinglan Wang1, Xuewei Li1, Ying Xu1, Xiao Zhang1, Yongping Mu1, Hua Zhang1, Shuang Huang3, Ping Liu4. 1. Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. 2. Traditional Chinese Medicine Department, First Affiliated Hospital of China Medical University, Shenyang, 201203, Liaoning, China. 3. Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, 32611, USA. shuanghuang@ufl.edu. 4. Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. liuliver@vip.sina.com.
Abstract
BACKGROUND: MicroRNAs have added a new dimension to our understanding of liver cirrhosis (LC) and associated processes like the activation of hepatic stellate cells (HSCs). METHODS: Serum samples were collected from 40 LC patients and 30 healthy donors. CCl4-induced LC mouse model in vivo and in vitro human HSC LX-2 and murine HSC JS-1 cells were researched. RESULTS: The levels of serum microRNA (miR)-744 is inversely correlated with the severity of LC and is a reliable biomarker of LC. In CCl4-induced LC model, the abundance of miR-744 was reduced in both sera and livers compared with sham controls. Importantly, increasing miR-744 abundance with synthetic miR-744 Agomir alleviated liver fibrosis, a critical component of LC, while reducing miR-744 with Antagomir exacerbated it. To elucidate molecular mechanism underlying the suppressive role of miR-744 in LC, we observed that miR-744 and transforming growth factor β1 (TGFβ1) are inversely correlated in LC patients' sera as well as sera/livers from CCl4-induced LC mice. We demonstrated that miR-744 Agomir downregulated the expression of TGFβ1 and further confirmed that TGFβ1 mRNA was a bona fide miR-744 target in HSCs. Moreover, miR-744 Agomir reduced the degree of F-actin formation and cell proliferation while miR-744 Antagomir promoted these events, suggesting that miR-744 is a negative regulator of HSC activation. CONCLUSIONS: MiR-744-led suppression in HSC activation is most likely through TGFβ1 because exogenous TGFβ1 nearly negated miR-744 Agomir's action. This study suggests that reduction of miR-744 is a reliable biomarker for LC and miR-744/TGFβ1 relationship is a key regulator of LC.
BACKGROUND: MicroRNAs have added a new dimension to our understanding of liver cirrhosis (LC) and associated processes like the activation of hepatic stellate cells (HSCs). METHODS: Serum samples were collected from 40 LCpatients and 30 healthy donors. CCl4-induced LCmouse model in vivo and in vitro humanHSCLX-2 and murineHSC JS-1 cells were researched. RESULTS: The levels of serum microRNA (miR)-744 is inversely correlated with the severity of LC and is a reliable biomarker of LC. In CCl4-induced LC model, the abundance of miR-744 was reduced in both sera and livers compared with sham controls. Importantly, increasing miR-744 abundance with synthetic miR-744Agomir alleviated liver fibrosis, a critical component of LC, while reducing miR-744 with Antagomir exacerbated it. To elucidate molecular mechanism underlying the suppressive role of miR-744 in LC, we observed that miR-744 and transforming growth factor β1 (TGFβ1) are inversely correlated in LCpatients' sera as well as sera/livers from CCl4-induced LCmice. We demonstrated that miR-744 Agomir downregulated the expression of TGFβ1 and further confirmed that TGFβ1 mRNA was a bona fide miR-744 target in HSCs. Moreover, miR-744 Agomir reduced the degree of F-actin formation and cell proliferation while miR-744 Antagomir promoted these events, suggesting that miR-744 is a negative regulator of HSC activation. CONCLUSIONS:MiR-744-led suppression in HSC activation is most likely through TGFβ1 because exogenous TGFβ1 nearly negated miR-744 Agomir's action. This study suggests that reduction of miR-744 is a reliable biomarker for LC and miR-744/TGFβ1 relationship is a key regulator of LC.
Authors: Hong Shen; Guojiang Huang; Mohammed Hadi; Patrick Choy; Manna Zhang; Gerald Y Minuk; Yongping Chen; Yuewen Gong Journal: Am J Physiol Gastrointest Liver Physiol Date: 2003-06-04 Impact factor: 4.052