Molecular Biology Reports

, Volume 41, Issue 7, pp 4513–4519 | Cite as

Profiles of serum microRNAs; miR-125b-5p and miR223-3p serve as novel biomarkers for HBV-positive hepatocellular carcinoma

  • Burcu Gurer Giray
  • Gurol Emekdas
  • Seda Tezcan
  • Mahmut Ulger
  • Mehmet Sami SerinEmail author
  • Orhan Sezgin
  • Engin Altintas
  • Eyup Naci Tiftik


Recently, circulating miRNAs have been reported as promising biomarkers for various pathologic conditions including cancer. Certain microRNAs (miRNAs) have been shown early diagnostic potential for many types of cancer. The objective of this study was to investigate the potential of certain serum/plasma miRNAs as novel non-invasive biomarkers for early diagnosis of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC). For this reason, the expression levels of 24 miRNA (let-7c, miR-92a-3p, 423-5p, 150-5p, 223-3p, 125b-5p, 342-3p, miR-206, 122-5p, 375, 223-5p, 10a-5p, 23b-5p, 99a-5p, 23a-5p, 10a-3p, 122-3p, 125b-1-3p, 23b-3p, 125b-2-3p, 23a-3p, 92a-1-5p, 92a-2-5p, 99a-3p) were analyzed in plasma of patients with chronic hepatitis B, HBV-positive cirrhosis and HBV-positive HCC and compared with control group samples. Totally 94 plasma samples; 28 control and 66 patient plasma (24 CHB, 22 HBV-positive cirrhosis, 20 HBV-positive HCC) and were included in this study. The expression levels of 24 miRNAs were detected for all control and patient group plasma samples by qRT-PCR using BioMark™ 96.96 Dynamic Array (Fluidigm Corporation) system. The expression levels of miR-125b-5p were detected 2.85 fold, 2.46 fold and 1.89 fold (p = 0.01513, p = 0.0009440, p = 0.0001446) up regulated in CHB, HBV-positive cirrhosis and HBV-positive HCC, respectively when compared versus control group individually by Mann–Whitney U test. The expression levels of miR-223-3p were detected 5.55 fold, 13.88 fold and 12.65 fold (p = 0.01513, p = 0.0009440, p = 0.0001446) down regulated in same comparisons. When all groups were compared versus control group by one-way ANOVA test, the expression levels of miR-223-3p were also found statistically significant (p < 0.05). Although not statistically significant, miR-125b-5p tended to be upregulated. (p = 0.07192). These results significantly imply that miR-125b-5p and miR223-3p could be used as novel non-invasive biomarkers of HBV-positive HCC in very early, even at CHB stage of liver disease.


Hepatocellular carcinoma miRNA HBV Early detection Tumor biomarker Diagnosis 



This study was supported by Grants from the Mersin University Scientific Research Funds, Mersin, Turkey [Project no. BAP-SBE TM (BGG) 2011-5 YL].


  1. 1.
    Ferlay J, Bray F, Pisani P, Parkin DM (2004) GLOBOCAN 2002: cancer incidence, mortality and prevalence worldwide, version 2.0, IARC cancerbase no. 5. IARC Press, LyonGoogle Scholar
  2. 2.
    Sun J, Haiqi LuH, Wang X, Jin H (2013) MicroRNAs in hepatocellular carcinoma: regulation function, and clinical implications. Sci World J 2013:924206. doi: 10.1155/2013/924206 Google Scholar
  3. 3.
    Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C (2006) Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis. Oncogene 25(27):3823–3833CrossRefPubMedGoogle Scholar
  4. 4.
    Zhu P, Tan D, Peng Z, Liu F, Song L (2007) Polymorphism analyses of hepatitis B virus X gene in hepatocellular carcinoma patients from southern China. Acta Biochim Biophys Sin (Shanghai) 39(4):265–272CrossRefGoogle Scholar
  5. 5.
    Ozen C, Yildiz G, Dagcan A, Cevik D, Ors A, Keles U, Topel H, Ozturk M (2013) Genetics and epigenetics of liver cancer. N Biotechnol 30(4):381–384. doi: 10.1016/j.nbt.2013.01.007 CrossRefPubMedGoogle Scholar
  6. 6.
    Zhou J, Yu L, Gao X, Hu J, Wang J, Dai Z, Wang JF, Zhang Z, Lu S, Huang X, Wang Z, Qiu S, Wang X, Yang G, Sun H, Tang Z, Wu Y, Zhu H, Fan J (2011) Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol 29(36):4781–4788CrossRefPubMedGoogle Scholar
  7. 7.
    Qi P, Cheng SQ, Wang H, Li N, Chen YF, Gao CF (2011) Serum microRNAs as biomarkers for hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. PLoS One 6(12):e28486. doi: 10.1371/journal.pone.0028486 PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Ura S, Honda M, Yamashita T, Ueda T, Takatori H, Nishino R, Sunakozaka H, Sakai Y, Horimoto K, Kaneko S (2009) Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. Hepatology 49(4):1098–1112CrossRefPubMedGoogle Scholar
  9. 9.
    Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF, Shen HB, Zhang CY, Zen K (2010) Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res 70(23):9798–9807CrossRefPubMedGoogle Scholar
  10. 10.
    Gorur A, Balci Fidanci S, Dogruer Unal N, Ayaz L, Akbayir S, Yildirim Yaroglu H, Dirlik M, Serin MS, Tamer L (2012) Determination of plasma microRNA for early detection of gastric cancer. Mol Biol Rep 40(3):2091–2096. doi: 10.1007/s11033-012-2267-7 CrossRefPubMedGoogle Scholar
  11. 11.
    Zinkin NT, Grall F, Bhaskar K, Otu HH, Spentzos D, Kalmowitz B, Wells M, Guerrero M, Asara JM, Libermann TA, Afdhal NH (2008) Serum proteomics and biomarkers in hepatocellular carcinoma and chronic liver disease. Clin Cancer Res 14(2):470–477CrossRefPubMedGoogle Scholar
  12. 12.
    Karakatsanis A, Papaconstantinou I, Gazouli M, Lyberopoulou A, Polymeneas G, Voros D (2013) Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol Carcinog 52(4):297–303CrossRefPubMedGoogle Scholar
  13. 13.
    Wong QW, Ching AK, Chan AW, Choy KW, To KF, Lai PB, Wong N (2010) MiR-222 overexpression confers cell migratory advantages in hepatocellular carcinoma through enhancing AKT signaling. Clin Cancer Res 16(3):867–875CrossRefPubMedGoogle Scholar
  14. 14.
    Han ZB, Zhong L, Teng MJ, Fan JW, Tang HM, Wu JY, Chen HY, Wang ZW, Qiu GQ, Peng ZH (2012) Identification of recurrence-related microRNAs in hepatocellular carcinoma following liver transplantation. Mol Oncol 6(4):445–457CrossRefPubMedGoogle Scholar
  15. 15.
    Li W, Xie L, He X, Li J, Tu K, Wei L, Wu J, Guo Y, Ma X, Zhang P, Pan Z, Hu X, Zhao Y, Xie H, Jiang G, Chen T, Wang J, Zheng S, Cheng J, Wan D, Yang S, Li Y, Gu J (2008) Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma. Int J Cancer 123(7):1616–1622CrossRefPubMedGoogle Scholar
  16. 16.
    Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K (2006) Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 25(17):2537–2545CrossRefPubMedGoogle Scholar
  17. 17.
    Qi J, Wang J, Katayama H, Sen S, Liu SM (2013) Circulating microRNAs (cmiRNAs) as novel potential biomarkers for hepatocellular carcinoma. Neoplasma 60(2):135–142PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Sun YM, Lin KY, Chen YQ (2013) Diverse functions of miR-125 family in different cell contexts. J Hematol Oncol 15(6):6. doi: 10.1186/1756-8722-6-6 CrossRefGoogle Scholar
  19. 19.
    Bousquet M, Nguyen D, Chen C, Shields L, Lodish HF (2012) MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA. Haematologica 97:1713–1721PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Bi Q, Tang S, Xia L, Du R, Fan R, Gao L, Jin J, Liang S, Chen Z, Xu G, Nie Y, Wu K, Liu J, Shi Y, Ding J, Fan D (2012) Ectopic expression of MiR-125a inhibits the proliferation and metastasis of hepatocellular carcinoma by targeting MMP11 and VEGF. PLoS One 7:e40169PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Xu N, Zhang L, Meisgen F, Harada M, Heilborn J, Homey B, Grander D, Stahle M, Sonkoly E, Pivarcsi A (2012) MicroRNA-125b down-regulates matrix metallopeptidase 13 and inhibits cutaneous squamous cell carcinoma cell proliferation, migration, and invasion. J Biol Chem 287:29899–29908PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Ge Y, Sun Y, Chen J (2011) IGF-II is regulated by microRNA-125b in skeletal myogenesis. J Cell Biol 192:69–81PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Burcu Gurer Giray
    • 1
  • Gurol Emekdas
    • 1
  • Seda Tezcan
    • 1
  • Mahmut Ulger
    • 1
  • Mehmet Sami Serin
    • 2
    Email author
  • Orhan Sezgin
    • 3
  • Engin Altintas
    • 3
  • Eyup Naci Tiftik
    • 4
  1. 1.Department of Medical Microbiology, Faculty of MedicineMersin UniversityMersinTurkey
  2. 2.Department of Pharmaceutical Microbiology, Faculty of PharmacyMersin UniversityMersinTurkey
  3. 3.Department of Gastroenterology, Faculty of MedicineMersin UniversityMersinTurkey
  4. 4.Department of Hematology, Faculty of MedicineMersin UniversityMersinTurkey

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