title: Long Non-coding RNA Growth Arrest-specific Transcript 5 (GAS5) Inhibits Liver Fibrogenesis through a Mechanism of Competing Endogenous RNA.
abstract: Effective control of hepatic stellate cell (HSC) activation and proliferation is critical to the treatment of liver fibrosis. Long non-coding RNAs have been shown to play a pivotal role in the regulation of cellular processes. It has been reported that growth arrest-specific transcript 5 (GAS5) acts as a crucial mediator in the control of cell proliferation and growth. However, little is known about the role and underlying mechanism of GAS5 in liver fibrosis. In this study, our results indicated that GAS5 expression was reduced in mouse, rat, and human fibrotic liver samples and in activated HSCs. Overexpression of GAS5 suppressed the activation of primary HSCs in vitro and alleviated the accumulation of collagen in fibrotic liver tissues in vivo. We identified GAS5 as a target of microRNA-222 (miR-222) and showed that miR-222 could inhibit the expression of GAS5. Interestingly, GAS5 could also repress miR-222 expression. A pulldown assay further validated that GAS5 could directly bind to miR-222. As a competing endogenous RNAs, GAS5 had no effect on primary miR-222 expression. In addition, GAS5 was mainly localized in the cytoplasm. Quantitative RT-PCR further demonstrated that the copy numbers of GAS5 per cell are higher than those of miR-222. GAS5 increased the level of p27 protein by functioning as a competing endogenous RNA for miR-222, thereby inhibiting the activation and proliferation of HSCs. Taken together, a new regulatory circuitry in liver fibrosis has been identified in which RNAs cross-talk by competing for shared microRNAs. Our findings may provide a new therapeutic strategy for liver fibrosis.
authors.affiliation: Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai 201508, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Yu
authors.affiliation: Wenzhou Key Laboratory of Surgery.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai 201508, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Departments of Infectious Diseases.
authors.forename: Peihong
authors.initials: P
authors.lastname: Dong
authors.affiliation: Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Hepatology, Ningbo Yinzhou Second Hospital, Ningbo 315000, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Chuanyong
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Zhanju
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai 201508, China; Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai 201508, China. Electronic address: ktsqdph@163.com.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fan
mesh_terms: D000818:Animals; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000502:physiology*
chemical_list: C561567:GAS5 long non-coding RNA, human; D062085:RNA, Long Noncoding; D012313:RNA
keywords: RNA interference (RNAi); competing endogenous RNA; fibrosis; growth arrest-specific transcript 5; hepatic stellate cell (HSC); liver fibrosis; long non-coding RNA (long ncRNA, lncRNA); microRNA (miRNA); microRNA-222