Clinical and Translational Oncology

, Volume 18, Issue 8, pp 841–847 | Cite as

Expression of serum miR-218 in hepatocellular carcinoma and its prognostic significance

  • L. Yang
  • Q. Xu
  • H. Xie
  • G. Gu
  • J. JiangEmail author
Research Article



Several recent studies have revealed that microRNAs (miRNAs) are stably detectable in the circulation and can be used as biomarkers for diagnosis and prognosis of malignancy. The aim of this manuscript is to investigate serum miR-218 expression in patients with hepatocellular carcinoma (HCC) and to analyze its potential diagnostic and prognostic value in HCC.


Quantitative real-time quantitative PCR (qPCR) was conducted to detect serum miR-218 expression from 156 HCC and 98 benign liver diseases (BLD) as well as 64 healthy controls. The relevance of serum miR-218 expression to the clinicopathological factors was assessed. In addition, the prediction of cutoff values of the markers was performed by the receiver operating characteristic (ROC) curve. Moreover, the Kaplan–Meier method was used to plot survival curves and univariable and multivariable Cox regression analyses were used to evaluate independent prognostic factors.


Consequently, our findings revealed that serum miR-218 levels were remarkably underexpressed in HCC patients as compared to BLD patients and healthy controls. And its low level was obviously related to tumor size (p = 0.048), tumor number (p = 0.018), vascular invasion (p = 0.039), Edmondson grade (p = 0.042), and higher TNM stage (III–IV). ROC curve analysis showed that miR-218 had a significant diagnostic accuracy, yielded an AUC (the areas under the ROC curve) of 0.734 (95 % confidence interval (CI) 0.68–0.789, p < 0.01), thus providing a sensitivity of 66.7 % and a specificity of 69.1 % in discriminating HCC from BLD and healthy controls. Meanwhile, miR-218 can act as a useful biomarker in distinguishing the patients with large tumors (>5 cm) from patients with small tumors (<5 cm) (p < 0.01). In addition, the combination of miR-218 and AFP had greater diagnosis capacity with an AUC of 0.908 (95 % CI 0.876–0.940; p < 0.01). Both log-rank test and Cox regression analysis demonstrated that the decreased serum expression of miR-218 had a significant impact on overall survival of the patients with HCC (HR = 3.049, 95 % CI 2.028–4.585, p < 0.01).


Taken together, this study suggested that serum expression of miR-218 might be a potential noninvasive tumor biomarker in the diagnosis and assessment of prognosis of HCC.


miR-218 Biomarker Prognostic marker Diagnostic marker Hepatocellular carcinoma 



This work was partly supported by the National Natural Science Foundation of China No. 81130057.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Research involving human participants

Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of Ningbo First hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Lai GY, Weinstein SJ, Taylor PR, McGlynn KA, Virtamo J, Gail MH, et al. Effects of alpha-tocopherol and beta-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the atbc study. Br J Cancer. 2014;111:2220–3.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Vilgrain V, Abdel-Rehim M, Sibert A, Ronot M. Clinical studies in hepatocellular carcinoma. Futur Oncol. 2014;10:13–6.CrossRefGoogle Scholar
  4. 4.
    Beste LA, Ioannou GN, Yang Y, Chang MF, Ross D, Dominitz JA. Improved surveillance for hepatocellular carcinoma with a primary care-oriented clinical reminder. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2015;13:172–9.Google Scholar
  5. 5.
    Ertle JM, Heider D, Wichert M, Keller B, Kueper R, Hilgard P, et al. A combination of alpha-fetoprotein and des-gamma-carboxy prothrombin is superior in detection of hepatocellular carcinoma. Digestion. 2013;87:121–31.CrossRefPubMedGoogle Scholar
  6. 6.
    Sharma A, Wu JC. MicroRNA expression profiling of human-induced pluripotent and embryonic stem cells. Methods Mol Biol. 2013;936:247–56.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ong SG, Lee WH, Kodo K, Wu JC. MicroRNA-mediated regulation of differentiation and trans-differentiation in stem cells. Adv drug Deliv Rev 2015.Google Scholar
  8. 8.
    Hebrant A, Floor S, Saiselet M, Antoniou A, Desbuleux A, Snyers B, et al. miRNA expression in anaplastic thyroid carcinomas. PLoS One. 2014;9:e103871.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gowrishankar B, Ibragimova I, Zhou Y, Slifker MJ, Devarajan K, Al-Saleem T, et al. MicroRNA expression signatures of stage, grade, and progression in clear cell rcc. Cancer Biol Ther. 2014;15:329–41.CrossRefPubMedGoogle Scholar
  10. 10.
    Fu Z, Qian F, Yang X, Jiang H, Chen Y, Liu S. Circulating miR-222 in plasma and its potential diagnostic and prognostic value in gastric cancer. Med Oncol. 2014;31:164.CrossRefPubMedGoogle Scholar
  11. 11.
    Meng FL, Wang W, Jia WD. Diagnostic and prognostic significance of serum miR-24-3p in hbv-related hepatocellular carcinoma. Med Oncol. 2014;31:177.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang Y, Han D, Wei W, Cao W, Zhang R, Dong Q, et al. MiR-218 inhibited growth and metabolism of human glioblastoma cells by directly targeting e2f2. Cell Mol Neurobiol 2015.Google Scholar
  13. 13.
    Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, et al. MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the robo1 receptor. PLoS Genet. 2010;6:e1000879.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zarogoulidis P, Petanidis S, Kioseoglou E, Domvri K, Anestakis D, Zarogoulidis K. MiR-205 and Mir-218 expression is associated with carboplatin chemoresistance and regulation of apoptosis via mcl-1 and survivin in lung cancer cells. Cell Signal. 2015;27:1576–88.CrossRefPubMedGoogle Scholar
  15. 15.
    Sui C, Xu F, Shen W, Geng L, Xie F, Dai B, et al. Overexpression of miR-218 inhibits hepatocellular carcinoma cell growth through ret. Tumour Biol J Int Soc Oncodev Biol Med. 2015;36:1511–8.CrossRefGoogle Scholar
  16. 16.
    Jiang Z, Song Q, Yang S, Zeng R, Li X, Jiang C, et al. Serum microRNA-218 is a potential biomarker for esophageal cancer. Cancer Biomark Sect A Dis Mark. 2015.Google Scholar
  17. 17.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative pcr and the 2(−ΔΔc(t)) method. Methods. 2001;25:402–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Shin VY, Chu KM. MiRNA as potential biomarkers and therapeutic targets for gastric cancer. World J Gastroenterol WJG. 2014;20:10432–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Barger JF, Nana-Sinkam SP. MicroRNA as tools and therapeutics in lung cancer. Respir Med. 2015;109:803–12.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kjersem JB, Ikdahl T, Lingjaerde OC, Guren T, Tveit KM, Kure EH. Plasma micrornas predicting clinical outcome in metastatic colorectal cancer patients receiving first-line oxaliplatin-based treatment. Mol Oncol. 2014;8:59–67.CrossRefPubMedGoogle Scholar
  21. 21.
    Davidson MR, Larsen JE, Yang IA, Hayward NK, Clarke BE, Duhig EE, et al. MicroRNA-218 is deleted and downregulated in lung squamous cell carcinoma. PLoS One. 2010;5:e12560.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Alajez NM, Lenarduzzi M, Ito E, Hui AB, Shi W, Bruce J, et al. MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the slit2-robo1 pathway. Cancer Res. 2011;71:2381–91.CrossRefPubMedGoogle Scholar
  23. 23.
    Lu YF, Zhang L, Waye MM, Fu WM, Zhang JF. MiR-218 mediates tumorigenesis and metastasis: perspectives and implications. Exp Cell Res. 2015;334:173–82.CrossRefPubMedGoogle Scholar
  24. 24.
    Hu Y, Xu K, Yague E. miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer. Breast Cancer Res Treat. 2015;151:269–80.CrossRefPubMedGoogle Scholar
  25. 25.
    Yamasaki T, Seki N, Yoshino H, Itesako T, Hidaka H, Yamada Y, et al. MicroRNA-218 inhibits cell migration and invasion in renal cell carcinoma through targeting caveolin-2 involved in focal adhesion pathway. J Urol. 2013;190:1059–68.CrossRefPubMedGoogle Scholar
  26. 26.
    Li BS, Zhao YL, Guo G, Li W, Zhu ED, Luo X, et al. Plasma micrornas, miR-223, miR-21 and miR-218, as novel potential biomarkers for gastric cancer detection. PLoS One. 2012;7:e41629.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yu H, Gao G, Jiang L, Guo L, Lin M, Jiao X, et al. Decreased expression of miR-218 is associated with poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol. 2013;6:2904–11.PubMedPubMedCentralGoogle Scholar
  28. 28.
    El-Serag HB, Kramer JR, Chen GJ, Duan Z, Richardson PA, Davila JA. Effectiveness of AFP and ultrasound tests on hepatocellular carcinoma mortality in HCV-infected patients in the USA. Gut. 2011;60:992–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Wang Y, Shen Z, Zhu Z, Han R, Huai M. Clinical values of AFP, GPC3 mRNA in peripheral blood for prediction of hepatocellular carcinoma recurrence following OLT: AFP, GPC3 mrna for prediction of HCC. Hepat Mon. 2011;11:195–9.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Odenthal M, Hee J, Gockel I, Sisic L, Schmitz J, Stoecklein NH, et al. Serum microRNA profiles as prognostic/predictive markers in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction. Int J Cancer J Int du cancer. 2015;137:230–7.CrossRefGoogle Scholar
  31. 31.
    Liu H, Zhu L, Liu B, Yang L, Meng X, Zhang W, et al. Genome-wide microRNA profiles identify miR-378 as a serum biomarker for early detection of gastric cancer. Cancer Lett. 2012;316:196–203.CrossRefPubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2015

Authors and Affiliations

  1. 1.Department of Hepatopancreatobiliary SurgeryNingbo First HospitalNingboChina

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