Serum MicroRNA-122 as A Prognostic Biomarker in Patients with Liver Cirrhosis
Keywords:
Micro RNA 122, MELD score, liver cirrhosis, qPCR, overall survival
Abstract
Background: Liver cirrhosis is associated with high morbidity and mortality. MicroRNAs (miRNAs), a class of endogenous small non-coding RNAs, are becoming increasingly recognized as crucial regulators in gene expression networks. In particular, a low serum miRNA-122 level was associated with hepatic decompensation so it can be used as a prognostic marker for liver decompensation.Aim of work : Circulating miRNA-12 was examined aiming to clarify its prongnostic value in patients with liver cirrhosis and to discover its relation with patient's survival.Methods: Gene expression level of miRNA 122 was extracted and assessed in sera of 100 patients with liver cirrhosis, using quantitative reverse-transcription PCR (qRT-PCR) . MiRNA 122 expression levels were comparedto liver function tests, MELD score, overall survival time and to different manifestation of decompensation.Results: Serum samples from patients with hepatic decompensation showed significant downregulation of miRNA122compared to those from patients with compensated liver cirrhosis. Patients with ascites, and hepatorenal syndrome had significantly lower miRNA-122 levels than patients without these complications.A univariateCox regression analysis revealed a significantassociation between miRNA-122 levels and overall survival Multivariate Cox regression analysis revealed that only miRNA-122 serum levels and platelet count wereindependent factor for survival. MiRNA-122 sensitivity and specificity for the predection of decompensation in cirrhotic patients were 100.0% and 90.1% respectively the best cut off point value of 0.892 (AUC= 0.9429)Conclusions: Serum miRNA-122 is a useful new independent prognostic marker in patients with liver cirrhosis..References
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30- Cermelli S, Ruggieri A, Marrero JA, Ioannou G, Beretta L.: Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One. 2011, 6:e23937.
31-Botta F, Giannini E, Romagnoli P, et al., MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: a European study. Gut. 2003, 52(1): 134–139.
32- Bureau C, Métivier S, D’Amico M, et al., Serum bilirubin and platelet count: A simple predictive model for survival in patients with refractory ascites treated by TIPS. Journal of Hepatology.2011,54: 901–907.
33- Afdhal N, McHutchison J, Brown R, et al., :Thrombocytopenia associated with chronic liver disease. Journal of Hepatology. 2008, 48: 1000–1007.
2-Ca´rdenas A and Gine`s P: Management of patients with cirrhosis awaiting liver transplantation. Gut.2011, 60: 412–421.
3-Garcia-Tsao G and Bosch J: Management of varices and varicealhemorrhagein cirrhosis. N Engl J Med.2010, 362: 823–832.
4- Wiesner RH: Patient selection in an era of donor liver shortage: CurrentUS policy. Nat ClinPractGastroenterolHepatol, 2005; 2: 24–30.
5-Chen H, Bai M, Qi X, Liu L, He C, Yin Z, et al.: Child-Na Score: A Predictive Model for Survival in Cirrhotic Patients with Symptomatic Portal Hypertension Treated with TIPS. PLoS ONE. 2013, 8(11): e79637.
•
6-Etheridge A, Lee I, Hood L, Galas D, Wang K.: Extracellular microRNA: A new source of biomarkers: Mutation Research.2011,717(1): 85-90.
7-Esquela-Kerscher A and Slack FJ :Oncomirs – microRNAs with a role incancer. Nat Rev Cancer.2006, 6: 259–269.
8-Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 2004; 116: 281-297.
9- Dykxhoorn DM and Lieberman J :The silent revolution: RNA interference as basic biology, research tool, and therapeutic. Annu. Rev. Med. 2005, 56: 401-423
10- Lewis AP and JoplingCL :Regulation and biological function of the liver-specific miR-122. Biochem. Soc. Trans. 2010, 38: 1553-1557.
11-Boutz DR, Collins PJ, Suresh U,Lu M, Ramírez CM, Fernández-Hernando C, et al., : Two-tieredapproach identifies a network of cancer and liver disease-related genes regulatedby miR-122. J BiolChem. 2011, 286: 18066–18078.
12. Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS.: Loss of miR-122 expression in liver cancer correlates with suppression of thehepatic phenotype and gain of metastatic properties. Oncogene.2009, 28: 3526–3536.
13- Scisciani C, Vossio S, GuerrieriF,Schinzari V , De Iaco R , D'Onorio de Meo P, et al.,: Transcriptional regulation of miR-224 upregulated in human HCCs by NFκB inflammatory pathways. J Hepatol.2012, 56: 855-861.
14- Li J, Ghazwani M, Zhang Y, Lu J, Li J, Fan J, et al., : MiR-122 regulates collagen production via targeting hepaticstellate cells and suppressing P4HA1 expression. J Hepatol.2013,58: 522-528.
15- Arroyo V, Ginès P, Gerbes AL, et al. : Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.Hepatology. 1996,23 (1): 164–176.
16- Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-DeltaDelta C(T))Method. Methods. 2001, 25, 402.
17- Sørensen HT, Thulstrup AM, Mellemkjar L, et al., Longterm survival and cause-specific mortality in patients with cirrhosis of the liver: a nationwide cohort study in Denmark. Journal of Clinical Epidemiology. 2003, 56(1): 88–93.
18- Trebicka J, Anadol E, Elfimova N, Strack I, Roggendorf M, Viazov S, et al. :Hepatic and serum levels of miR-122 after chronic HCV-induced fibrosis. J. Hepatol. 2013, 58:234-239.
19- Wang K, Zhang S, Weber J, Baxter D, Galas DJ.: Export of microRNAs and microRNA-protective protein by mammalian cells. Nucl Acids Res. 2010, 38: 7248–7259.
20- Halász T, Horváth G, Pár G, et al., MiR-122 negatively correlates with liver fibrosis as detected by histology and FibroScan. World J Gastroenterol, 2015; 21(25): 7814-7823.
21- Hu J, Xu Y, Hao J, Wang S, Li C, Meng S.: MiR-122 in hepatic function and liver diseases. Protein Cell. 2012, 3: 364-371
22- Waidmann O, Kberle V, Brunner F,Zeuzem S, Piiper A, Kronenberger B. : Serum MicroRNA-122 Predicts Survival in Patients with Liver Cirrhosis PLoS ONE, 2012, 7(9): e45652.
23- Ko¨berle V, Kronenberger B, Pleli T, et al.,: Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. European Journal of Cancer. 2013, 49(16): 3442-3449.
24- Kholeif H, MohamedAboulEla A, Badawy D : Circulating Micro RNA-122 in Hepatitis C Virus Infected in Egyptian Group of Patients Clinical Medicine and Diagnostics. 2015, 5(6): 114-121.
25- Starkey PJ, Dear J, Platt V, et al., :Circulating microRNAs as potential markers of human drug induced liver injury. Hepatology.2011, 5: 1767–1776.
26- AbdElmouttaleb AT, Abd-Elatif DM, Soliman GM, Taher MS, Abonar AA. : Serum Micro RNA-122 as a Biomarker for Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients. Research In Cancer and Tumor. 2015, 4(2): 25-33.
27- Ding X, Ding J, Ning J,Yi F, Chen J, Zhao D, et al., : Circulating microRNA-122 as a potential biomarker for liver injury. Mol Med Rep. 2012, 5(6):1428-1432.
28-Jung CJ, Iyengar S, Blahnik KR, et al., : Epigenetic modulation of miR-122 facilitates human embryonic stem cell selfrenewal and hepatocellular carcinoma proliferation. PLoS One. 2011,6(11):e27740.
29-Bihrer V, Friedrich-Rust M, Kronenberger B, et al., : Serum miR- 122 as a biomarker of necroinflammation in patients with chronic hepatitis C virus infection. Am J Gastroenterol, 2011, 106: 1663–1669.
30- Cermelli S, Ruggieri A, Marrero JA, Ioannou G, Beretta L.: Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One. 2011, 6:e23937.
31-Botta F, Giannini E, Romagnoli P, et al., MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: a European study. Gut. 2003, 52(1): 134–139.
32- Bureau C, Métivier S, D’Amico M, et al., Serum bilirubin and platelet count: A simple predictive model for survival in patients with refractory ascites treated by TIPS. Journal of Hepatology.2011,54: 901–907.
33- Afdhal N, McHutchison J, Brown R, et al., :Thrombocytopenia associated with chronic liver disease. Journal of Hepatology. 2008, 48: 1000–1007.
Published
2016-12-28
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