Skip to main content
SpringerLink
Log in

Identification of circulating MicroRNAs as novel potential biomarkers for hepatocellular carcinoma detection: a systematic review and meta-analysis

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

MicroRNAs (miRNAs) in body fluids such as serum and plasma can be stably detected and used as potential biomarkers in hepatocellular carcinoma (HCC) diagnosis.

Objective

To systematically evaluate circulating miRNAs from HCC expression profiling studies and to determine miRNA biomarkers for HCC detection.

Methods

A systematic review and meta-analysis of published studies were carried out for comparing the circulating miRNA expressions between HCC patients and healthy people, hepatitis, or cirrhosis patients. A miRNA ranking system that considered the number of comparisons in agreement and total number of samples was used. Then the summary receiver-operating characteristic curve (sROC) results of the top miRNAs were combined to further evaluate their diagnostic value using Meta-disc 1.4.

Results

In the 17 included studies, three circulating miRNAs (miR-21, miR-122, and miR-223) were repeatedly reported three times or more in both HCC patients vs. healthy controls and vs. other hepatitis or cirrhosis patients. In further analysis, the area under curve (AUC) of sROC for miR-21, miR-122 and miR-223 in discriminating HCC patients from healthy people are 0.9293, 0.8128, and 0.8597, respectively.

Conclusions

Circulating miR-21 has highest level of diagnostic efficiency among three miRNAs candidate biomarkers (miR-21, miR-122, and miR-223) for detection of HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Venook AP, Papandreou C, Furuse J, de Guevara LL. The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist. 2010;15(Suppl 4):5–13. doi:10.1634/theoncologist.2010-S4-05.

    Article  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107.

    Article  PubMed  Google Scholar 

  3. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55. doi:10.1016/s0140-6736(11)61347-0.

    Article  PubMed  Google Scholar 

  4. Behne T, Copur MS. Biomarkers for hepatocellular carcinoma. Int J Hepatol. 2012;2012:859076. doi:10.1155/2012/859076.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Masuzaki R, Karp SJ, Omata M. New serum markers of hepatocellular carcinoma. Semin Oncol. 2012;39(4):434–9. doi:10.1053/j.seminoncol.2012.05.009.

    Article  CAS  PubMed  Google Scholar 

  6. Ba MC, Long H, Tang YQ, Cui SZ. GP73 expression and its significance in the diagnosis of hepatocellular carcinoma: a review. Int J Clin Exp Pathol. 2012;5(9):874–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Du Y, Liu M, Gao J, Li Z. Aberrant microRNAs expression patterns in pancreatic cancer and their clinical translation. Cancer Biother Radiopharm. 2013;28(5):361–9. doi:10.1089/cbr.2012.1389.

    Article  CAS  PubMed  Google Scholar 

  8. Costello E, Greenhalf W, Neoptolemos JP. New biomarkers and targets in pancreatic cancer and their application to treatment. Nat Rev Gastroenterol Hepatol. 2012;9(8):435–44. doi:10.1038/nrgastro.2012.119.

    Article  CAS  PubMed  Google Scholar 

  9. Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005;123(4):631–40. doi:10.1016/j.cell.2005.10.022.

    Article  CAS  PubMed  Google Scholar 

  10. Yates LA, Norbury CJ, Gilbert RJ. The long and short of microRNA. Cell. 2013;153(3):516–9. doi:10.1016/j.cell.2013.04.003.

    Article  CAS  PubMed  Google Scholar 

  11. Blanco-Calvo M, Calvo L, Figueroa A, Haz-Conde M, Anton-Aparicio L, Valladares-Ayerbes M. Circulating microRNAs: molecular microsensors in gastrointestinal cancer. Sensors Basel Switz. 2012;12(7):9349–62. doi:10.3390/s120709349.

    Article  CAS  Google Scholar 

  12. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105(30):10513–8. doi:10.1073/pnas.0804549105.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol. 2008;141(5):672–5. doi:10.1111/j.1365-2141.2008.07077.x.

    Article  PubMed  Google Scholar 

  14. Griffith OL, Melck A, Jones SJ, Wiseman SM. Meta-analysis and meta-review of thyroid cancer gene expression profiling studies identifies important diagnostic biomarkers. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(31):5043–51. doi:10.1200/jco.2006.06.7330.

    Article  CAS  Google Scholar 

  15. Chan SK, Griffith OL, Tai IT, Jones SJ. Meta-analysis of colorectal cancer gene expression profiling studies identifies consistently reported candidate biomarkers. Cancer Epidemiol Biomark Prevent A Public Am Assoc Cancer Res Cospon Am Soc Prevent Oncol. 2008;17(3):543–52. doi:10.1158/1055-9965.epi-07-2615.

    Article  CAS  Google Scholar 

  16. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003;3:25. doi:10.1186/1471-2288-3-25.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Littenberg B, Moses LE. Estimating diagnostic accuracy from multiple conflicting reports: a new meta-analytic method. Med Dec Making An Int J Soc Med Dec Making. 1993;13(4):313–21.

    Article  CAS  Google Scholar 

  18. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ Clin Res Ed. 1997;315(7109):629–34.

    Article  CAS  Google Scholar 

  19. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions. Cochrane Collaboration and John Wiley: Cochrane Handbook for Systematic Reviews of Interventions; 2008.

    Book  Google Scholar 

  20. Abdalla MA, Haj-Ahmad Y. Promising Candidate Urinary MicroRNA Biomarkers for the Early Detection of Hepatocellular Carcinoma among High-Risk Hepatitis C Virus Egyptian Patients. J Cancer. 2012;3:19–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Bihrer V, Waidmann O, Friedrich-Rust M, Forestier N, Susser S, Haupenthal J, et al. Serum microRNA-21 as marker for necroinflammation in hepatitis C patients with and without hepatocellular carcinoma. PLoS ONE. 2011;6(10):e26971. doi:10.1371/journal.pone.0026971.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Fu Y, Wei X, Tang C, Li J, Liu R, Shen A, et al. Circulating microRNA-101 as a potential biomarker for hepatitis B virus-related hepatocellular carcinoma. Oncol Lett. 2013;6(6):1811–5. doi:10.3892/ol.2013.1638.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Giray BG, Emekdas G, Tezcan S, Ulger M, Serin MS, Sezgin O, et al. Profiles of serum microRNAs; miR-125b-5p and miR223-3p serve as novel biomarkers for HBV-positive hepatocellular carcinoma. Mol Biol Rep. 2014;. doi:10.1007/s11033-014-3322-3.

    PubMed  Google Scholar 

  24. Gui J, Tian Y, Wen X, Zhang W, Zhang P, Gao J, et al. Serum microRNA characterization identifies miR-885-5p as a potential marker for detecting liver pathologies. Clin Sci Lond. 2011;120(5):183–93. doi:10.1042/cs20100297.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Koberle V, Kronenberger B, Pleli T, Trojan J, Imelmann E, Peveling-Oberhag J, et al. Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur J Cancer. 2013;49(16):3442–9. doi:10.1016/j.ejca.2013.06.002.

    Article  PubMed  Google Scholar 

  26. Li J, Wang Y, Yu W, Chen J, Luo J. Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance. Biochem Biophys Res Commun. 2011;406(1):70–3. doi:10.1016/j.bbrc.2011.01.111.

    Article  CAS  PubMed  Google Scholar 

  27. Li L, Guo Z, Wang J, Mao Y, Gao Q. Serum miR-18a: a potential marker for hepatitis B virus-related hepatocellular carcinoma screening. Dig Dis Sci. 2012;57(11):2910–6. doi:10.1007/s10620-012-2317-y.

    Article  CAS  PubMed  Google Scholar 

  28. Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF, et al. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res. 2010;70(23):9798–807. doi:10.1158/0008-5472.can-10-1001.

    Article  CAS  PubMed  Google Scholar 

  29. Liu AM, Yao TJ, Wang W, Wong KF, Lee NP, Fan ST, et al. Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open. 2012;2(2):e000825. doi:10.1136/bmjopen-2012-000825.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Qi P, Cheng SQ, Wang H, Li N, Chen YF, Gao CF. Serum microRNAs as biomarkers for hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. PLoS One. 2011;6(12):e28486. doi:10.1371/journal.pone.0028486.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Qu KZ, Zhang K, Li H, Afdhal NH, Albitar M. Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol. 2011;45(4):355–60. doi:10.1097/MCG.0b013e3181f18ac2.

    Article  CAS  PubMed  Google Scholar 

  32. Tomimaru Y, Eguchi H, Nagano H, Wada H, Kobayashi S, Marubashi S, et al. Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J Hepatol. 2012;56(1):167–75. doi:10.1016/j.jhep.2011.04.026.

    Article  CAS  PubMed  Google Scholar 

  33. Xu J, Wu C, Che X, Wang L, Yu D, Zhang T, et al. Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog. 2011;50(2):136–42. doi:10.1002/mc.20712.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang ZJ, Ge SX, Wang XM, Yuan Q, Yan Q, Ye HM, et al. Serum miR-483-5p as a potential biomarker to detect hepatocellular carcinoma. Hep Intl. 2013;7(1):199–207. doi:10.1007/s12072-012-9341-z.

    Article  Google Scholar 

  35. Zheng JJ, Yu FJ, Dong PH, Bai YH, Chen BC. Expression of miRNA-29b and its clinical significances in primary hepatic carcinoma. Zhonghua Yi Xue Za Zhi. 2013;93(12):888–91.

    CAS  PubMed  Google Scholar 

  36. Zhou J, Yu L, Gao X, Hu J, Wang J, Dai Z, et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(36):4781–8. doi:10.1200/jco.2011.38.2697.

    Article  CAS  Google Scholar 

  37. Hu QY, Jiang H, Su J, Jia YQ. MicroRNAs as biomarkers for hepatocellular carcinoma: a diagnostic meta-analysis. Clin Lab. 2013;59(9–10):1113–20.

    PubMed  Google Scholar 

  38. Yang Y, Zhu R. Diagnostic value of circulating microRNAs for hepatocellular carcinoma. Mol Biol Rep. 2014;. doi:10.1007/s11033-014-3578-7.

    Google Scholar 

  39. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133(2):647–58. doi:10.1053/j.gastro.2007.05.022.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Mar-Aguilar F, Mendoza-Ramirez JA, Malagon-Santiago I, Espino-Silva PK, Santuario-Facio SK, Ruiz-Flores P, et al. Serum circulating microRNA profiling for identification of potential breast cancer biomarkers. Dis Markers. 2013;34(3):163–9. doi:10.3233/dma-120957.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Si H, Sun X, Chen Y, Cao Y, Chen S, Wang H, et al. Circulating microRNA-92a and microRNA-21 as novel minimally invasive biomarkers for primary breast cancer. J Cancer Res Clin Oncol. 2013;139(2):223–9. doi:10.1007/s00432-012-1315-y.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Shen J, Todd NW, Zhang H, Yu L, Lingxiao X, Mei Y, et al. Plasma microRNAs as potential biomarkers for non-small-cell lung cancer. Lab Invest A J Tech Method Pathol. 2011;91(4):579–87. doi:10.1038/labinvest.2010.194.

    Article  CAS  Google Scholar 

  43. Wei J, Gao W, Zhu CJ, Liu YQ, Mei Z, Cheng T, et al. Identification of plasma microRNA-21 as a biomarker for early detection and chemosensitivity of non-small cell lung cancer. Chin J Cancer. 2011;30(6):407–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Kanaan Z, Rai SN, Eichenberger MR, Roberts H, Keskey B, Pan J, et al. Plasma miR-21: a potential diagnostic marker of colorectal cancer. Ann Surg. 2012;256(3):544–51. doi:10.1097/SLA.0b013e318265bd6f.

    Article  PubMed  Google Scholar 

  45. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27(15):2128–36. doi:10.1038/sj.onc.1210856.

    Article  CAS  PubMed  Google Scholar 

  46. Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem. 2008;283(2):1026–33. doi:10.1074/jbc.M707224200.

    Article  CAS  PubMed  Google Scholar 

  47. Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 2007;282(19):14328–36. doi:10.1074/jbc.M611393200.

    Article  CAS  PubMed  Google Scholar 

  48. ElHefnawi M, Soliman B, Abu-Shahba N, Amer M. An integrative meta-analysis of microRNAs in hepatocellular carcinoma. Genom Proteom Bioinform. 2013;11(6):354–67. doi:10.1016/j.gpb.2013.05.007.

    Article  CAS  Google Scholar 

  49. Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007;26(19):2799–803. doi:10.1038/sj.onc.1210083.

    Article  CAS  PubMed  Google Scholar 

  50. Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65(14):6029–33. doi:10.1158/0008-5472.can-05-0137.

    Article  CAS  PubMed  Google Scholar 

  51. Yao Q, Xu H, Zhang QQ, Zhou H, Qu LH. MicroRNA-21 promotes cell proliferation and down-regulates the expression of programmed cell death 4 (PDCD4) in HeLa cervical carcinoma cells. Biochem Biophys Res Commun. 2009;388(3):539–42. doi:10.1016/j.bbrc.2009.08.044.

    Article  CAS  PubMed  Google Scholar 

  52. Lou Y, Yang X, Wang F, Cui Z, Huang Y. MicroRNA-21 promotes the cell proliferation, invasion and migration abilities in ovarian epithelial carcinomas through inhibiting the expression of PTEN protein. Int J Mol Med. 2010;26(6):819–27.

    Article  CAS  PubMed  Google Scholar 

  53. Li T, Li D, Sha J, Sun P, Huang Y. MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochem Biophys Res Commun. 2009;383(3):280–5. doi:10.1016/j.bbrc.2009.03.077.

    Article  CAS  PubMed  Google Scholar 

  54. Fassan M, Pizzi M, Giacomelli L, Mescoli C, Ludwig K, Pucciarelli S, et al. PDCD4 nuclear loss inversely correlates with miR-21 levels in colon carcinogenesis. Virchows Archiv An Int J Pathol. 2011;458(4):413–9. doi:10.1007/s00428-011-1046-5.

    Article  CAS  Google Scholar 

  55. Wang P, Zou F, Zhang X, Li H, Dulak A, Tomko RJ Jr, et al. microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Cancer Res. 2009;69(20):8157–65. doi:10.1158/0008-5472.can-09-1996.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA. 2011;108(12):5003–8. doi:10.1073/pnas.1019055108.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13(4):423–33. doi:10.1038/ncb2210.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. McDonald JS, Milosevic D, Reddi HV, Grebe SK, Algeciras-Schimnich A. Analysis of circulating microRNA: preanalytical and analytical challenges. Clin Chem. 2011;57(6):833–40. doi:10.1373/clinchem.2010.157198.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Natural Science Foundation of China (NO. 81260445, 30960332) and Program of key Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, China (GK2014-ZZ04, GK2013-13-A-01-02).

Conflict of interest

The authors report no declarations of interest.

Author information

Author notes

    Authors and Affiliations

    1. Medical Scientific Research Center, Guangxi Medical University, Nanning, 530021, China

      G. Li & D. Li

    2. School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi, 530021, China

      C. Li, J. Chen & M. He

    3. Department of Pharmacy, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China

      Q. Shen

    4. Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Guangxi Medical University, Ministry of Education, Guangxi, China

      M. He

    Authors
    1. G. Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Q. Shen
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. C. Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. D. Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. J. Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. M. He
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to M. He.

    Additional information

    G. Li and Q. Shen contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Li, G., Shen, Q., Li, C. et al. Identification of circulating MicroRNAs as novel potential biomarkers for hepatocellular carcinoma detection: a systematic review and meta-analysis. Clin Transl Oncol 17, 684–693 (2015). https://doi.org/10.1007/s12094-015-1294-y

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12094-015-1294-y

    Keywords

    Search

    Navigation