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Serum miR-18a: A Potential Marker for Hepatitis B Virus-Related Hepatocellular Carcinoma Screening

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Abstract

Background

Alpha-fetoprotein detection is currently mainly used in clinic for diagnosis of primary hepatocellular carcinoma (HCC). However, its sensitivity and specificity are not satisfying. Approximately 60–80 % of patients with HCC have an established background of chronic infection with hepatitis B virus (HBV).

Aims

To investigate the potential of serum microRNAs (miRNAs) as biomarkers for HBV-related HCC.

Methods

This study was divided into two phases: firstly, marker (miR-95, miR-18a, miR-10b, miR125a, and miR-378) detection by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in sera from HBV patients with HCC (n = 15) and health subject (n = 15); and, secondly, marker validation by real-time qRT-PCR on HBV patients with HCC (n = 86) or hepatitis or cirrhosis (n = 30), and healthy subject (n = 45).

Results

Serum miR-18a was significantly higher in HBV patients with HCC than healthy controls (p < 0.01); serum miR-378 was significantly lower in HBV patients with HCC compared to healthy control (p < 0.05). Receiver operating characteristic (ROC) curve analyses suggested that serum miR-18a had significant diagnostic value for HBV-related HCC. MiR-18a yielded an area under the curve (AUC) of ROC of 0.881 with 86.1 % sensitivity and 75.0 % specificity in discriminating HBV-related HCC from healthy controls, and an AUC of ROC of 0.775 with 77.2 % sensitivity and 70.0 % specificity in discriminating HBV-related HCC from chronic hepatitis or cirrhosis.

Conclusions

Our results suggest that serum miR-18a might serve as a novel and potential noninvasive biomarker for HBV-related HCC screening.

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References

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

    Article  CAS  Google Scholar 

  2. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–2576.

    Article  CAS  PubMed  Google Scholar 

  3. Poon D, Anderson BO, Chen LT, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian oncology summit 2009. Lancet Oncol. 2009;10:1111–1118.

    Article  PubMed  Google Scholar 

  4. Nam SW, Jung JJ, Bae SH, et al. Clinical outcomes of delayed clearance of serum HBsAG in patients with chronic HBV infection. Korean J Intern Med. 2007;22:73–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Zinkin NT, Grall F, Bhaskar K, et al. Serum proteomics and biomarkers in hepatocellular carcinoma and chronic liver disease. Clin Cancer Res. 2008;14:470–477.

    Article  CAS  PubMed  Google Scholar 

  6. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–297.

    Article  CAS  PubMed  Google Scholar 

  7. Valencia-Sanchez MA, Liu J, Hannon GJ, et al. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20:515–524.

    Article  CAS  PubMed  Google Scholar 

  8. Miska EA. How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev. 2005;15:563–568.

    Article  CAS  PubMed  Google Scholar 

  9. Kutay H, Bai S, Datta J, et al. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem. 2006;99:671–678.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Chen Q, Chen X, Zhang M, et al. miR-137 is frequently down-regulated in gastric cancer and is a negative regulator of Cdc42. Dig Dis Sci. 2011;56:2009–2016.

    Article  CAS  PubMed  Google Scholar 

  11. Wu W, Sun M, Zou GM, et al. MicroRNA and cancer: current status and prospective. Int J Cancer. 2007;120:953–960.

    Article  CAS  PubMed  Google Scholar 

  12. Visone R, Petrocca F, Croce CM. Micro-RNAs in gastrointestinal and liver disease. Gastroenterology. 2008;135:1866–1869.

    Article  CAS  PubMed  Google Scholar 

  13. Iorio MV, Casalini P, Piovan C, et al. MicroRNA-205 regulates HER3 in human breast cancer. Cancer Res. 2009;69:2195–2200.

    Article  CAS  PubMed  Google Scholar 

  14. Garzon R, Heaphy CE, Havelange V, et al. MicroRNA 29b functions in acute myeloid leukemia. Blood. 2009;114:5331–5341.

    Article  CAS  PubMed  Google Scholar 

  15. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–866.

    Article  CAS  PubMed  Google Scholar 

  16. Chen X, Ba Y, Ma L, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18:997–1006.

    Article  CAS  PubMed  Google Scholar 

  17. Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105:10513–10518.

    Article  CAS  PubMed  Google Scholar 

  18. Li A, Omura N, Hong SM, et al. Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. Cancer Res. 2010;70:5226–5237.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Gui J, Tian Y, Wen X, et al. Serum microRNA characterization identifies miR-885-5p as a potential marker for detecting liver pathologies. Clin Sci (Lond). 2011;120:183–193.

    Article  CAS  Google Scholar 

  20. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408.

    Article  CAS  PubMed  Google Scholar 

  21. Pineau P, Volinia S, McJunkin K, et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci USA. 2010;107:264–269.

    Article  CAS  PubMed  Google Scholar 

  22. Murakami Y, Yasuda T, Saigo K, et al. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 2006;25:2537–2545.

    Article  CAS  PubMed  Google Scholar 

  23. Ladeiro Y, Couchy G, Balabaud C, et al. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 2008;47:1955–1963.

    Article  CAS  PubMed  Google Scholar 

  24. Li W, Xie L, He X, et al. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma. Int J Cancer. 2008;23:1616–1622.

    Article  Google Scholar 

  25. Li Y, Tan W, Neo TW, et al. Role of the miR-106b-25 microRNA cluster in hepatocellular carcinoma. Cancer Sci. 2009;100:1234–1242.

    Article  CAS  PubMed  Google Scholar 

  26. Lawrie CH, Gal S, Dunlop HM, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol. 2008;141:672–675.

    Article  PubMed  Google Scholar 

  27. Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One. 2008;3:e3148.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Chin LJ, Slack FJ. A truth serum for cancer–microRNAs have major potential as cancer biomarkers. Cell Res. 2008;18:983–984.

    Article  CAS  PubMed  Google Scholar 

  29. Zheng D, Haddadin S, Wang Y, et al. Plasma microRNAs as novel biomarkers for early detection of lung cancer. Int J Clin Exp Pathol. 2011;4:575–586.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Shigehara K, Yokomuro S, Ishibashi O, et al. Real-time PCR-based analysis of the human bile microRNAome identifies miR-9 as a potential diagnostic biomarker for biliary tract cancer. PLoS One. 2011;6:e23584.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Kanemaru H, Fukushima S, Yamashita J, et al. The circulating microRNA-221 level in patients with malignant melanoma as a new tumor marker. J Dermatol Sci. 2011;61:187–193.

    Article  CAS  PubMed  Google Scholar 

  32. Qi P, Cheng SQ, Wang H, et al. Serum MicroRNAs as biomarkers for hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. PLoS One. 2011;6:e28486.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Li LM, Hu ZB, Zhou ZX, et al. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res. 2010;70:9798–9807.

    Article  CAS  PubMed  Google Scholar 

  34. Woods K, Thomson JM, Hammond SM. Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors. J Biol Chem. 2007;282:2130–2134.

    Article  CAS  PubMed  Google Scholar 

  35. Yao Y, Suo AL, Li ZF, et al. MicroRNA profiling of human gastric cancer. Mol Med Rep. 2009;2:963–970.

    CAS  PubMed  Google Scholar 

  36. Guo J, Miao Y, Xiao B, et al. Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J Gastroenterol Hepatol. 2009;24:652–657.

    Article  CAS  PubMed  Google Scholar 

  37. Motoyama K, Inoue H, Takatsuno Y, et al. Over- and under- expressed microRNAs in human colorectal cancer. Int J Oncol. 2009;34:1069–1075.

    CAS  PubMed  Google Scholar 

  38. Wang YX, Zhang XY, Zhang BF, et al. Initial study of microRNA expression profiles of colonic cancer without lymph node metastasis. J Dig Dis. 2010;11:50–54.

    Article  PubMed  Google Scholar 

  39. Szafranska AE, Davison TS, John J, et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene. 2007;26:4442–4452.

    Article  CAS  PubMed  Google Scholar 

  40. Gao W, Shen H, Liu L, et al. MiR-21 overexpression in human primary squamous cell lung carcinoma is associated with poor patient prognosis. J Cancer Res Clin Oncol. 2011;137:557–665.

    Article  CAS  PubMed  Google Scholar 

  41. Nam EJ, Yoon H, Kim SW, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res. 2008;14:2690–2695.

    Article  CAS  PubMed  Google Scholar 

  42. Nam EJ, Yoon H, Kim SW, et al. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Nasopharyngeal carcinoma. Gastroenterology. 2009;136:683–693.

    Article  Google Scholar 

  43. Takakura S, Mitsutake N, Nakashima M, et al. Oncogenic role of miR-17-92 cluster in anaplastic thyroid cancer cells. Cancer Sci. 2008;99:1147–1154.

    Article  CAS  PubMed  Google Scholar 

  44. Leivonen SK, Mäkelä R, Ostling P, et al. Protein lysate microarray analysis to identify microRNAs regulating estrogen receptor signaling in breast cancer cell lines. Oncogene. 2009;28:3926–3936.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This work was supported by grants from the Hospital Administration Center of Wuxi, China (No.YGZ1016, YGZ1106).

Conflict of interest

This study has not financial or other conflict of interest.

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Correspondence to Zijan Guo or Qi Gao.

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Li, L., Guo, Z., Wang, J. et al. Serum miR-18a: A Potential Marker for Hepatitis B Virus-Related Hepatocellular Carcinoma Screening. Dig Dis Sci 57, 2910–2916 (2012). https://doi.org/10.1007/s10620-012-2317-y

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  • DOI: https://doi.org/10.1007/s10620-012-2317-y

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