Skip to main content
Log in

Diagnostic value of circulating microRNAs for hepatocellular carcinoma

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Much evidence indicates that microRNAs could play potential roles as diagnostic and prognostic biomarkers of human cancers, including hepatocellular carcinoma (HCC). The present meta-analysis aimed to systematically evaluate the diagnostic accuracy of circulating microRNAs for HCC. Eligible studies were identified through multiple search strategies and assessed for relevance and quality. Results from different studies were pooled using random-effects models. The quality of each study was scored with the revised quality assessment of diagnostic accuracy studies tool. The summary receiver operator characteristic (SROC) curve and other measures were used to assess the overall performance of microRNA-based assays. Evidence of heterogeneity was evaluated using the I 2 test. Meta-regressions were conducted to analyze potential sources of heterogeneity. Deeks’ test was used to test for potential publication bias. Thirty studies from 13 publications, including 1,314 patients with HCC and 1,407 controls, comprised healthy individuals and patients with hepatitis B/C or cirrhosis, were included in this meta-analysis. For diagnostic meta-analysis, the overall pooled results were as follows: sensitivity was 0.80 (95 % CI 0.74–0.84), specificity was 0.81 (95 % CI 0.74–0.87), positive likelihood ratio was 4.2 (95 % CI 3.0–6.0), negative likelihood ratio was 0.25 (95 % CI 0.19–0.38) and diagnostic odds ratio was 17 (95 % CI 10–29). The area under the SROC curve was 0.86 (95 % CI 0.84–0.90). Subgroup analyses suggested that multiple microRNAs had much better accuracy than single microRNA. Our findings suggest that circulating microRNAs show significant potential as diagnostic markers of HCC, particularly when using multiple microRNAs. However the results of this meta-analysis justify larger, more rigorous studies to confirm our conclusions.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

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

    Article  PubMed  Google Scholar 

  2. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108

    Article  PubMed  Google Scholar 

  3. Yuen MF, Hou JL, Chutaputti A (2009) Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol 24(3):346–353

    Article  PubMed  Google Scholar 

  4. Kew MC (2010) Epidemiology of chronic hepatitis B virus infection, hepatocellular carcinoma, and hepatitis B virus-induced hepatocellular carcinoma. Pathol Biol (Paris) 58(4):273–277

    Article  CAS  Google Scholar 

  5. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576

    Article  CAS  PubMed  Google Scholar 

  6. 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):470–477

    Article  CAS  PubMed  Google Scholar 

  7. Schwartz M, Roayaie S, Konstadoulakis M (2007) Strategies for the management of hepatocellular carcinoma. Nat Clin Pract Oncol 4(7):424–432

    Article  CAS  PubMed  Google Scholar 

  8. Fukuda S, Itamoto T, Nakahara H, Kohashi T, Ohdan H, Hino H, Ochi M, Tashiro H, Asahara T (2005) Clinicopathologic features and prognostic factors of resected solitary small-sized hepatocellular carcinoma. Hepatogastroenterology 52(64):1163–1167

    PubMed  Google Scholar 

  9. Yuen MF, Cheng CC, Lauder IJ, Lam SK, Ooi CG, Lai CL (2000) Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 31(2):330–335

    Article  CAS  PubMed  Google Scholar 

  10. Benson AB, Abrams TA, Ben-Josef E, Bloomston PM, Botha JF, Clary BM, Covey A, Curley SA, D’Angelica MI, Davila R, Ensminger WD, Gibbs JF, Laheru D, Malafa MP, Marrero J, Meranze SG, Mulvihill SJ, Park JO, Posey JA, Sachdev J, Salem R, Sigurdson ER, Sofocleous C, Vauthey JN, Venook AP, Goff LW, Yen Y, Zhu AX (2009) NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Cancer Netw 7(4):350–391

    CAS  Google Scholar 

  11. Liu AM, Yao TJ, Wang W, Wong KF, Lee NP, Fan ST, Poon RT, Gao C, Luk JM (2012) Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open 2(2):e000825

    Article  PubMed Central  PubMed  Google Scholar 

  12. Johnson PJ (2001) The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis 5(1):145–159

    Article  CAS  PubMed  Google Scholar 

  13. el-Houseini ME, Mohammed MS, Elshemey WM, Hussein TD, Desouky OS, Elsayed AA (2005) Enhanced detection of hepatocellular carcinoma. Cancer Control 12(4):248–253

    PubMed  Google Scholar 

  14. Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–355

    Article  CAS  PubMed  Google Scholar 

  15. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854

    Article  CAS  PubMed  Google Scholar 

  16. Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM (2006) MicroRNA expression and function in cancer. Trends Mol Med 12(12):580–587

    Article  CAS  PubMed  Google Scholar 

  17. Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6(11):857–866

    Article  CAS  PubMed  Google Scholar 

  18. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, Li Q, Li X, Wang W, Wang J, Jiang X, Xiang Y, Xu C, Zheng P, Zhang J, Li R, Zhang H, Shang X, Gong T, Ning G, Zen K, Zhang CY (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18(10):997–1006

    Article  CAS  PubMed  Google Scholar 

  19. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105(30):10513–10518

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. 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):9798–9807

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Xu J, Wu C, Che X, Wang L, Yu D, Zhang T, Huang L, Li H, Tan W, Wang C, Lin D (2011) Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog 50(2):136–142

    Article  CAS  PubMed  Google Scholar 

  23. 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):4781–4788

    Article  CAS  PubMed  Google Scholar 

  24. Li L, Guo Z, Wang J, Mao Y, Gao Q (2012) Serum miR-18a: a potential marker for hepatitis B virus-related hepatocellular carcinoma screening. Dig Dis Sci 57(11):2910–2916

    Article  CAS  PubMed  Google Scholar 

  25. Luo J, Chen M, Huang H, Yuan T, Zhang M, Zhang K, Deng S (2013) Circulating microRNA-122a as a diagnostic marker for hepatocellular carcinoma. Onco Targets Ther 6:577–583

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Wei R, Huang GL, Zhang MY, Li BK, Zhang HZ, Shi M, Chen XQ, Huang L, Zhou QM, Jia WH, Zheng XF, Yuan YF, Wang HY (2013) Clinical significance and prognostic value of microRNA expression signatures in hepatocellular carcinoma. Clin Cancer Res 19(17):4780–4791

    Article  CAS  PubMed  Google Scholar 

  27. Qu KZ, Zhang K, Li H, Afdhal NH, Albitar M (2011) Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol 45(4):355–360

    Article  CAS  PubMed  Google Scholar 

  28. Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM (2008) Systematic reviews of diagnostic test accuracy. Ann Intern Med 149(12):889–897

    Article  PubMed Central  PubMed  Google Scholar 

  29. Barker FG 2nd, Carter BS (2005) Synthesizing medical evidence: systematic reviews and metaanalyses. Neurosurg Focus 19(4):E5

    Article  PubMed  Google Scholar 

  30. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155(8):529–536

    Article  PubMed  Google Scholar 

  31. Deville WL, Buntinx F, Bouter LM, Montori VM, de Vet HC, van der Windt DA, Bezemer PD (2002) Conducting systematic reviews of diagnostic studies: didactic guidelines. BMC Med Res Methodol 2:9

    Article  PubMed Central  PubMed  Google Scholar 

  32. Mitchell AJ, Vaze A, Rao S (2009) Clinical diagnosis of depression in primary care: a meta-analysis. Lancet 374(9690):609–619

    Article  PubMed  Google Scholar 

  33. Walter SD (2002) Properties of the summary receiver operating characteristic (SROC) curve for diagnostic test data. Stat Med 21(9):1237–1256

    Article  CAS  PubMed  Google Scholar 

  34. Jones CM, Athanasiou T (2005) Summary receiver operating characteristic curve analysis techniques in the evaluation of diagnostic tests. Ann Thorac Surg 79(1):16–20

    Article  PubMed  Google Scholar 

  35. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed Central  PubMed  Google Scholar 

  36. Dinnes J, Deeks J, Kirby J, Roderick P (2005) A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy. Health Technol Assess 9(12):1–113 iii

    Article  CAS  Google Scholar 

  37. Deeks JJ, Macaskill P, Irwig L (2005) The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol 58(9):882–893

    Article  PubMed  Google Scholar 

  38. Abdalla MA, Haj-Ahmad Y (2012) Promising candidate urinary microRNA biomarkers for the early detection of hepatocellular carcinoma among high-risk hepatitis C virus Egyptian patients. J Cancer 3:19–31

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Tomimaru Y, Eguchi H, Nagano H, Wada H, Kobayashi S, Marubashi S, Tanemura M, Tomokuni A, Takemasa I, Umeshita K, Kanto T, Doki Y, Mori M (2012) Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J Hepatol 56(1):167–175

    Article  CAS  PubMed  Google Scholar 

  40. Liang Z, Gao Y, Shi W, Zhai D, Li S, Jing L, Guo H, Liu T, Wang Y, Du Z (2013) Expression and significance of microRNA-183 in hepatocellular carcinoma. ScientificWorldJournal 2013:381874

    PubMed Central  PubMed  Google Scholar 

  41. Shen J, Wang A, Wang Q, Gurvich I, Siegel AB, Remotti H, Santella RM (2013) Exploration of genome-wide circulating microRNA in hepatocellular carcinoma: miR-483-5p as a potential biomarker. Cancer Epidemiol Biomarkers Prev 22(12):2364–2373

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Li T, Yin J, Yuan L, Wang S, Yang L, Du X, Lu J (2014) Downregulation of microRNA-139 is associated with hepatocellular carcinoma risk and short-term survival. Oncol Rep 31:1699–1706

    CAS  PubMed  Google Scholar 

  43. Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M (2008) MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology 47(4):1223–1232

    Article  CAS  PubMed  Google Scholar 

  44. He QY, Zhu R, Lei T, Ng MY, Luk JM, Sham P, Lau GK, Chiu JF (2008) Toward the proteomic identification of biomarkers for the prediction of HBV related hepatocellular carcinoma. J Cell Biochem 103(3):740–752

    Article  CAS  PubMed  Google Scholar 

  45. Collier J, Sherman M (1998) Screening for hepatocellular carcinoma. Hepatology 27(1):273–278

    Article  CAS  PubMed  Google Scholar 

  46. Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PM (2003) The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol 56(11):1129–1135

    Article  PubMed  Google Scholar 

  47. Deeks JJ, Altman DG (2004) Diagnostic tests 4: likelihood ratios. BMJ 329(7458):168–169

    Article  PubMed Central  PubMed  Google Scholar 

  48. Wang D, Mou ZY, Zhai JX, Zong HX, Zhao XD (2008) Application of Stata software to test heterogeneity in meta-analysis method. Zhonghua Liu Xing Bing Xue Za Zhi 29(7):726–729

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the National Natural Sciences Foundation of China (No. 81102692).

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rui Zhu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Zhu, R. Diagnostic value of circulating microRNAs for hepatocellular carcinoma. Mol Biol Rep 41, 6919–6929 (2014). https://doi.org/10.1007/s11033-014-3578-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-014-3578-7

Keywords

Navigation