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MicroRNAs as a novel class of diagnostic biomarkers in detection of hepatocellular carcinoma: a meta-analysis

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Tumor Biology

Abstract

MicroRNAs (miRNAs) have been proposed as promising diagnostic biomarkers for many diseases, particularly in the field of cancer research. Numerous studies have explored the use of miRNAs in the detection of hepatocellular carcinoma (HCC), with some reporting inconsistent results. Thus, we conducted this meta-analysis to evaluate the potential diagnostic value of miRNAs in HCC. All relevant literature was collected from the PubMed and other databases before June 3, 2014. The summary receiver operator characteristic (SROC) curve and other parameters were used to estimate overall predictive performance. Fourteen studies involving 1,848 cases with HCC and 1,187 controls (576 healthy controls and 611 individuals with chronic liver diseases) were included in this meta-analysis. SROC analyses for the diagnostic power of miRNAs yielded an area under the curve (AUC) of 0.93 with 86 % sensitivity and 86 % specificity in discriminating patients with HCC from healthy subjects and an AUC of 0.88 with 79 % sensitivity and 83 % specificity in differentiating patients with HCC from those with chronic liver diseases (CLDs). Furthermore, subgroup analyses showed that miRNA panels yielded excellent diagnostic characteristics, with an AUC of 0.99 (96 % sensitivity and 96 % specificity) for detection of HCC from healthy controls and an AUC of 0.93 (85 % sensitivity and 88 % specificity) for HCC from those with CLDs. MiRNAs might be novel potential biomarkers for the diagnosis of HCC, and a combination of multiple miRNAs could significantly improve the diagnostic accuracy.

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References

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

    Google Scholar 

  2. McGlynn KA, London WT. The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis. 2011;15:223–43. doi:10.1016/j.cld.2011.03.006. vii-x.

    PubMed  PubMed Central  Google Scholar 

  3. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45:529–38. doi:10.1016/j.jhep.2006.05.013.

    PubMed  Google Scholar 

  4. 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:e000825. doi:10.1136/bmjopen-2012-000825.

    PubMed  PubMed Central  Google Scholar 

  5. Gramantieri L, Fornari F, Callegari E, Sabbioni S, Lanza G, Croce CM, et al. MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med. 2008;12:2189–204. doi:10.1111/j.1582-4934.2008.00533.x.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Benson 3rd AB, Abrams TA, Ben-Josef E, Bloomston PM, Botha JF, Clary BM, et al. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Cancer Netw. 2009;7:350–91.

    CAS  Google Scholar 

  7. 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;56:167–75. doi:10.1016/j.jhep.2011.04.026.

    CAS  PubMed  Google Scholar 

  8. Oka H, Tamori A, Kuroki T, Kobayashi K, Yamamoto S. Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology. 1994;19:61–6.

    CAS  PubMed  Google Scholar 

  9. Weidhaas JB, Babar I, Nallur SM, Trang P, Roush S, Boehm M, et al. MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res. 2007;67:11111–6. doi:10.1158/0008-5472.CAN-07-2858.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D, et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci U S A. 2008;105:12885–90. doi:10.1073/pnas.0806202105.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kato M, Paranjape T, Muller RU, Nallur S, Gillespie E, Keane K, et al. The mir-34 microRNA is required for the DNA damage response in vivo in C. elegans and in vitro in human breast cancer cells. Oncogene. 2009;28:2419–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Trang P, Medina PP, Wiggins JF, Ruffino L, Kelnar K, Omotola M, et al. Regression of murine lung tumors by the let-7 microRNA. Oncogene. 2010;29:1580–7. doi:10.1038/onc.2009.445.

    CAS  PubMed  Google Scholar 

  13. Abd-El-Fattah AA, Sadik NA, Shaker OG, Aboulftouh ML. Differential microRNAs expression in serum of patients with lung cancer, pulmonary tuberculosis, and pneumonia. Cell Biochem Biophys. 2013;67:875–84. doi:10.1007/s12013-013-9575-y.

    CAS  PubMed  Google Scholar 

  14. Sanfiorenzo C, Ilie MI, Belaid A, Barlesi F, Mouroux J, Marquette CH, et al. Two panels of plasma microRNAs as non-invasive biomarkers for prediction of recurrence in resectable NSCLC. PLoS One. 2013;8:e54596. doi:10.1371/journal.pone.0054596.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20:515–24. doi:10.1101/gad.1399806.

    CAS  PubMed  Google Scholar 

  16. Inui M, Martello G, Piccolo S. MicroRNA control of signal transduction. Nat Rev Mol Cell Biol. 2010;11:252–63. doi:10.1038/nrm2868.

    CAS  PubMed  Google Scholar 

  17. Chen CJ, Lee MH. Early diagnosis of hepatocellular carcinoma by multiple microRNAs: validity, efficacy, and cost-effectiveness. J Clin Oncol. 2011;29:4745–7. doi:10.1200/jco.2011.39.0054.

    CAS  PubMed  Google Scholar 

  18. Dillhoff M, Liu J, Frankel W, Croce C, Bloomston M. MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J Gastrointest Surg. 2008;12:2171–6. doi:10.1007/s11605-008-0584-x.

    PubMed  PubMed Central  Google Scholar 

  19. Cai H, Yuan Y, Hao YF, Guo TK, Wei X, Zhang YM. Plasma microRNAs serve as novel potential biomarkers for early detection of gastric cancer. Med Oncol. 2013;30:452. doi:10.1007/s12032-012-0452-0.

    PubMed  Google Scholar 

  20. Liu GH, Zhou ZG, Chen R, Wang MJ, Zhou B, Li Y, et al. Serum miR-21 and miR-92a as biomarkers in the diagnosis and prognosis of colorectal cancer. Tumour Biol. 2013. doi:https://doi.org/10.1007/s13277-013-0753-8.

    Article  PubMed  Google Scholar 

  21. Ng EK, Li R, Shin VY, Jin HC, Leung CP, Ma ES, et al. Circulating microRNAs as specific biomarkers for breast cancer detection. PLoS One. 2013;8:e53141. doi:10.1371/journal.pone.0053141.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang Z, Miao R, Li G, Wu Y, Robson SC, Yang X, et al. Identification of recurrence related microRNAs in hepatocellular carcinoma after surgical resection. Int J Mol Sci. 2013;14:1105–18. doi:10.3390/ijms14011105.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 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;49:3442–9. doi:10.1016/j.ejca.2013.06.002.

    PubMed  Google Scholar 

  24. Gu H, Guo X, Zou L, Zhu H, Zhang J. Upregulation of microRNA-372 associates with tumor progression and prognosis in hepatocellular carcinoma. Mol Cell Biochem. 2013;375:23–30. doi:10.1007/s11010-012-1521-6.

    CAS  PubMed  Google Scholar 

  25. 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:e28486. doi:10.1371/journal.pone.0028486.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 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;50:136–42. doi:10.1002/mc.20712.

    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;57:2910–6. doi:10.1007/s10620-012-2317-y.

    CAS  PubMed  Google Scholar 

  28. Luo J, Chen M, Huang H, Yuan T, Zhang M, Zhang K, et al. Circulating microRNA-122a as a diagnostic marker for hepatocellular carcinoma. Onco Targets Ther. 2013;6:577–83. doi:10.2147/ott.s44215.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Li T, Yin J, Yuan L, Wang S, Yang L, Du X, et al. Downregulation of microRNA-139 is associated with hepatocellular carcinoma risk and short-term survival. Oncol Rep. 2014. doi:https://doi.org/10.3892/or.2014.3032.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 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;70:9798–807. doi:10.1158/0008-5472.can-10-1001.

    CAS  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;45:355–60. doi:10.1097/MCG.0b013e3181f18ac2.

    CAS  PubMed  Google Scholar 

  32. 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. 2011;29:4781–8. doi:10.1200/jco.2011.38.2697.

    CAS  PubMed  Google Scholar 

  33. Shen J, Wang A, Wang Q, Gurvich I, Siegel AB, Remotti H, et al. Exploration of genome-wide circulating microRNA in hepatocellular carcinoma: MiR-483-5p as a potential biomarker. Cancer Epidemiol Biomarkers Prev. 2013;22:2364–73. doi:10.1158/1055-9965.epi-13-0237.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Wei R, Huang GL, Zhang MY, Li BK, Zhang HZ, Shi M, et al. Clinical significance and prognostic value of microRNA expression signatures in hepatocellular carcinoma. Clin Cancer Res. 2013;19:4780–91. doi:10.1158/1078-0432.ccr-12-2728.

    CAS  PubMed  Google Scholar 

  35. 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.

    CAS  PubMed  Google Scholar 

  36. Liang Z, Gao Y, Shi W, Zhai D, Li S, Jing L, et al. Expression and significance of microRNA-183 in hepatocellular carcinoma. ScientificWorldJournal. 2013;2013:381874. doi:10.1155/2013/381874.

    PubMed  PubMed Central  Google Scholar 

  37. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529–36. doi:10.7326/0003-4819-155-8-201110180-00009.

    PubMed  Google Scholar 

  38. Chu H, Guo H. A unification of models for meta-analysis of diagnostic accuracy studies. Biostatistics. 2009;10:201–3. doi:10.1093/biostatistics/kxn040.

    PubMed  Google Scholar 

  39. Walter SD. Properties of the summary receiver operating characteristic (SROC) curve for diagnostic test data. Stat Med. 2002;21:1237–56. doi:10.1002/sim.1099.

    CAS  PubMed  Google Scholar 

  40. Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol. 2005;58:882–93. doi:10.1016/j.jclinepi.2005.01.016.

    PubMed  Google Scholar 

  41. Huang S, He X. The role of microRNAs in liver cancer progression. Br J Cancer. 2011;104:235–40. doi:10.1038/sj.bjc.6606010.

    CAS  PubMed  Google Scholar 

  42. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36. doi:10.1002/hep.20933.

    PubMed  Google Scholar 

  43. Wang Y, Gao X, Wei F, Zhang X, Yu J, Zhao H, et al. Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis. Gene. 2014;533:389–97. doi:10.1016/j.gene.2013.09.038.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, 324 Jingwu Weiqi Road, Jinan, 250021, China

    Hongmin Yin & Chengyong Qin

  2. Department of Gastroenterology, Binzhou Central Hospital Shandong Province, Binzhou, 251700, China

    Hongmin Yin, Peng Ren, Bo Cheng & Shumin Li

  3. Clinical laboratory, Affiliated Hospital of Binzhou Medical College, Binzhou, 256603, China

    Xinguo Peng

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  1. Hongmin Yin
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Correspondence to Chengyong Qin.

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Yin, H., Peng, X., Ren, P. et al. MicroRNAs as a novel class of diagnostic biomarkers in detection of hepatocellular carcinoma: a meta-analysis. Tumor Biol. 35, 12317–12326 (2014). https://doi.org/10.1007/s13277-014-2544-2

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