MicroRNA-9 limits hepatic fibrosis by suppressing the activation and proliferation of hepatic stellate cells by directly targeting MRP1/ABCC1 Retraction in /10.3892/or.2023.8590

Sun,Jie; Zhang,Huanying; Li,Liying; Yu,Lianfeng; Fu,Lifang

doi:10.3892/or.2017.5382

MicroRNA-9 limits hepatic fibrosis by suppressing the activation and proliferation of hepatic stellate cells by directly targeting MRP1/ABCC1

Retraction in: /10.3892/or.2023.8590

Authors:
- Jie Sun
- Huanying Zhang
- Liying Li
- Lianfeng Yu
- Lifang Fu
View Affiliations

Affiliations: Department of Traditional Chinese Medicine, Shandong Medical College, Linyi, Shandong 276000, P.R. China, Department of Respiration, Affiliated Hospital of Shandong Medical College, Linyi, Shandong 276000, P.R. China, Department of Rehabilitation Medicine, Shandong Medical College, Linyi, Shandong 276000, P.R. China, Department of Anatomy, Shandong Medical College, Linyi, Shandong 276000, P.R. China, Department of Respiration, Chinese Medicine Hospital of Linyi City, Linyi, Shandong 276000, P.R. China
Published online on: January 17, 2017 https://doi.org/10.3892/or.2017.5382
Pages: 1698-1706

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Liver fibrosis is a chronic liver disease characterized by the proliferation and activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix (ECM). Research suggests that microRNAs (miRNAs) are a new type of regulator of liver fibrosis. In the present study, we investigated the role of microRNA-9 (miR-9) in the process of liver fibrosis, as well as the underlying mechanism of action. Downregulated levels of miR-9 were found in fibrotic liver tissues and activated HSCs as detected by qRT-PCR; whereas, expression of multidrug resistance‑associated protein 1 (MRP1/ABCC1) was upregulated in the fibrotic liver tissues and activated HSCs. CCK-8 and BrdU assays revealed that miR-9 reduced the proliferative ability of the HSCs. In addition, expression levels of ECM-related genes (α-SMA, Col-1 and Timp-1), which are markers of HSC activation, were downregulated by miR-9. Conversely, an miR-9 inhibitor promoted cell proliferation and HSC activation. In addition, a luciferase reporter assay indicated that miR-9 targets the 3'-untranslated region (3'-UTR) of MRP1 and causes a significant decrease in MRP1. miR-9 inhibited the activation of the Hedgehog (Hh) pathway and the expression of MRP1, while this suppression was rescued by the overexpression of MRP1. Finally, a CCl4-induced mouse model of liver fibrosis was used to investigate the effects of miR-9 on liver fibrosis in vivo. The results showed that miR-9 abrogated hepatic fibrosis by suppressing the expression of MRP1 in CCl4-induced liver fibrotic mice. In conclusion, the present study demonstrated that miR-9 suppresses the proliferation and activation of HSCs through the Hh pathway by targeting MRP1, which suggests that miR-9 has therapeutic potential for liver fibrosis.

View Figures

View References

1	Kim Y, Ejaz A, Tayal A, Spolverato G, Bridges JF, Anders RA and Pawlik TM: Temporal trends in population-based death rates associated with chronic liver disease and liver cancer in the United States over the last 30 years. Cancer. 120:3058–3065. 2014. View Article : Google Scholar : PubMed/NCBI
2	Popov Y and Schuppan D: Targeting liver fibrosis: Strategies for development and validation of antifibrotic therapies. Hepatology. 50:1294–1306. 2009. View Article : Google Scholar : PubMed/NCBI
3	Fagone P, Mangano K, Pesce A, Portale TR, Puleo S and Nicoletti F: Emerging therapeutic targets for the treatment of hepatic fibrosis. Drug Discov Today. 21:369–375. 2016. View Article : Google Scholar : PubMed/NCBI
4	Fagone P, Mangano K, Mammana S, Pesce A, Pesce A, Caltabiano R, Giorlandino A, Portale TR, Cavalli E, Lombardo GA, et al: Identification of novel targets for the diagnosis and treatment of liver fibrosis. Int J Mol Med. 36:747–752. 2015.PubMed/NCBI
5	Puche JE, Saiman Y and Friedman SL: Hepatic stellate cells and liver fibrosis. Compr Physiol. 3:1473–1492. 2013. View Article : Google Scholar : PubMed/NCBI
6	Lade A, Noon LA and Friedman SL: Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer. Curr Opin Oncol. 26:100–107. 2014. View Article : Google Scholar : PubMed/NCBI
7	Peverill W, Powell LW and Skoien R: Evolving concepts in the pathogenesis of NASH: Beyond steatosis and inflammation. Int J Mol Sci. 15:8591–8638. 2014. View Article : Google Scholar : PubMed/NCBI
8	König J, Hartel M, Nies AT, Martignoni ME, Guo J, Büchler MW, Friess H and Keppler D: Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int J Cancer. 115:359–367. 2005. View Article : Google Scholar : PubMed/NCBI
9	Borst P and Elferink RO: Mammalian ABC transporters in health and disease. Annu Rev Biochem. 71:537–592. 2002. View Article : Google Scholar : PubMed/NCBI
10	Ros JE, Roskams TA, Geuken M, Havinga R, Splinter PL, Petersen BE, LaRusso NF, van der Kolk DM, Kuipers F, Faber KN, et al: ATP binding cassette transporter gene expression in rat liver progenitor cells. Gut. 52:1060–1067. 2003. View Article : Google Scholar : PubMed/NCBI
11	Jeon BH, Lee YH, Yun MR, Kim SH, Lee BW, Kang ES, Lee HC and Cha BS: Increased expression of ATP-binding cassette transporter A1 (ABCA1) as a possible mechanism for the protective effect of cilostazol against hepatic steatosis. Metabolism. 64:1444–1453. 2015. View Article : Google Scholar : PubMed/NCBI
12	Hannivoort RA, Dunning S, Borght S Vander, Schroyen B, Woudenberg J, Oakley F, Buist-Homan M, van den Heuvel FA, Geuken M, Geerts A, et al: Multidrug resistance-associated proteins are crucial for the viability of activated rat hepatic stellate cells. Hepatology. 48:624–634. 2008. View Article : Google Scholar : PubMed/NCBI
13	Hayes CN and Chayama K: MicroRNAs as biomarkers for liver disease and hepatocellular carcinoma. Int J Mol Sci. 17:2802016. View Article : Google Scholar : PubMed/NCBI
14	Kitano M and Bloomston PM: Hepatic stellate cells and microRNAs in pathogenesis of liver fibrosis. J Clin Med. 5:52016. View Article : Google Scholar :
15	Szabo G and Bala S: MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol. 10:542–552. 2013. View Article : Google Scholar : PubMed/NCBI
16	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
17	Li G, Li J, Li C, Qi H, Dong P, Zheng J and Yu F: MicroRNA-125a-5p contributes to hepatic stellate cell activation through targeting FIH1. Cell Physiol Biochem. 38:1544–1552. 2016. View Article : Google Scholar : PubMed/NCBI
18	Omenetti A, Choi S, Michelotti G and Diehl AM: Hedgehog signaling in the liver. J Hepatol. 54:366–373. 2011. View Article : Google Scholar : PubMed/NCBI
19	Choi SS, Omenetti A, Syn WK and Diehl AM: The role of Hedgehog signaling in fibrogenic liver repair. Int J Biochem Cell Biol. 43:238–244. 2011. View Article : Google Scholar : PubMed/NCBI
20	Chen Y, Choi SS, Michelotti GA, Chan IS, Swiderska-Syn M, Karaca GF, Xie G, Moylan CA, Garibaldi F, Premont R, et al: Hedgehog controls hepatic stellate cell fate by regulating metabolism. Gastroenterology. 143:1319–1329.e1-11. 2012. View Article : Google Scholar : PubMed/NCBI
21	Rombouts K and Carloni V: Determination and characterization of tetraspanin-associated phosphoinositide-4 kinases in primary and neoplastic liver cells. Methods Mol Biol. 1376:203–212. 2016. View Article : Google Scholar : PubMed/NCBI
22	Görbig MN, Ginès P, Bataller R, Nicolás JM, Garcia-Ramallo E, Cejudo P, Sancho-Bru P, Jiménez W, Arroyo V and Rodés J: Human hepatic stellate cells secrete adrenomedullin: Potential autocrine factor in the regulation of cell contractility. J Hepatol. 34:222–229. 2001. View Article : Google Scholar : PubMed/NCBI
23	Jalan R, De Chiara F, Balasubramaniyan V, Andreola F, Khetan V, Malago M, Pinzani M, Mookerjee RP and Rombouts K: Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension. J Hepatol. 64:823–833. 2016. View Article : Google Scholar : PubMed/NCBI
24	Hyun J, Wang S, Kim J, Rao KM, Park SY, Chung I, Ha CS, Kim SW, Yun YH and Jung Y: MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression. Nat Commun. 7:109932016. View Article : Google Scholar : PubMed/NCBI
25	Roderburg C, Urban GW, Bettermann K, Vucur M, Zimmermann H, Schmidt S, Janssen J, Koppe C, Knolle P, Castoldi M, et al: Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology. 53:209–218. 2011. View Article : Google Scholar : PubMed/NCBI
26	Zhang DW, Zhao YX, Wei D, Li YL, Zhang Y, Wu J, Xu J, Chen C, Tang H, Zhang W, et al: HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis. J Hepatol. 57:1283–1291. 2012. View Article : Google Scholar : PubMed/NCBI
27	Friedman SL: Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med. 328:1828–1835. 1993. View Article : Google Scholar : PubMed/NCBI
28	Abu-Elsaad NM and Elkashef WF: Modified citrus pectin stops progression of liver fibrosis by inhibiting galectin-3 and inducing apoptosis of stellate cells. Can J Physiol Pharmacol. 94:554–562. 2016. View Article : Google Scholar : PubMed/NCBI
29	Gao B, Chang C, Zhou J, Zhao T, Wang C, Li C and Gao G: Pycnogenol protects against rotenone-induced neurotoxicity in PC12 cells through regulating NF-κB-iNOS signaling pathway. DNA Cell Biol. 34:643–649. 2015. View Article : Google Scholar : PubMed/NCBI
30	Yan G, Li B, Xin X, Xu M, Ji G and Yu H: MicroRNA-34a promotes hepatic stellate cell activation via targeting ACSL1. Med Sci Monit. 21:3008–3015. 2015. View Article : Google Scholar : PubMed/NCBI
31	Ji J, Zhang J, Huang G, Qian J, Wang X and Mei S: Over-expressed microRNA-27a and 27b influence fat accumulation and cell proliferation during rat hepatic stellate cell activation. FEBS Lett. 583:759–766. 2009. View Article : Google Scholar : PubMed/NCBI
32	Wang L, Ma L, Fan H, Yang Z, Li L and Wang H: MicroRNA-9 regulates cardiac fibrosis by targeting PDGFR-β in rats. J Physiol Biochem. 72:213–223. 2016. View Article : Google Scholar : PubMed/NCBI
33	Liu C, Yuan X, Tao L, Cheng Z, Dai X, Sheng X and Xue D: Xia-yu-xue decoction (XYXD) reduces carbon tetrachloride (CCl4)-induced liver fibrosis through inhibition hepatic stellate cell activation by targeting NF-κB and TGF-β1 signaling pathways. BMC Complement Altern Med. 15:2012015. View Article : Google Scholar : PubMed/NCBI
34	Xu L, Hui AY, Albanis E, Arthur MJ, O'Byrne SM, Blaner WS, Mukherjee P, Friedman SL and Eng FJ: Human hepatic stellate cell lines, LX-1 and LX-2: New tools for analysis of hepatic fibrosis. Gut. 54:142–151. 2005. View Article : Google Scholar : PubMed/NCBI
35	Omenetti A, Popov Y, Jung Y, Choi SS, Witek RP, Yang L, Brown KD, Schuppan D and Diehl AM: The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut. 57:1275–1282. 2008. View Article : Google Scholar : PubMed/NCBI
36	Fleig SV, Choi SS, Yang L, Jung Y, Omenetti A, VanDongen HM, Huang J, Sicklick JK and Diehl AM: Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice. Lab Invest. 87:1227–1239. 2007. View Article : Google Scholar : PubMed/NCBI
37	Choi SS, Omenetti A, Witek RP, Moylan CA, Syn WK, Jung Y, Yang L, Sudan DL, Sicklick JK, Michelotti GA, et al: Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis. Am J Physiol Gastrointest Liver Physiol. 297:G1093–G1106. 2009. View Article : Google Scholar : PubMed/NCBI
38	Lian N, Jiang Y, Zhang F, Jin H, Lu C, Wu X, Lu Y and Zheng S: Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells. Lab Invest. 95:790–803. 2015. View Article : Google Scholar : PubMed/NCBI
39	Zhang Y, Laterra J and Pomper MG: Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp. Neoplasia. 11:96–101. 2009. View Article : Google Scholar : PubMed/NCBI