Skip to main content
Log in

Reanalysis of microRNA expression profiles identifies novel biomarkers for hepatocellular carcinoma prognosis

  • Original Article
  • Published:
Tumor Biology

Abstract

The aim of our study is to identify microRNAs (miRNAs) that have significance in the prognosis and pathogenesis of hepatocellular carcinoma (HCC). The miRNAs differentially expressed in HCC were examined by using a human miRNA microarray dataset, and then the acquired candidates were screened by another microarray dataset. As a result, we got 25 miRNAs which were aberrantly expressed in cancer and meanwhile predicated distinct prognosis. Among them, miR-139-5p was down-regulated in HCC and its low expression in cancer tissue meant poor prognosis. Additionally, we demonstrated that its low expression was also related to several clinicopathologic characteristics such as vein invasion, BCLC stage, p-AKT expression, and pIGFR1 expression. In vitro, it has been discovered that treatment of HCC cells with a miR-139-5p mimic lead to inhibition of cell growth and migration. Moreover, luciferase assay showed that KPNA4 was not the direct target of miR-139-5p. Ectopic expression of miR-139-5p has not repressed the expression of KPNA4, but inhibited the nuclear import of NF-κB and phosphorylation of Akt. In conclusion, for the first time, we identify 25 deregulated miRNAs that are associated with prognosis and prove that miR-139-5p functions as a tumor suppressor in HCC and its low expression predicts poor prognosis.

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

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.

    Article  PubMed  Google Scholar 

  2. Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005;5(11):845–56.

    Article  CAS  PubMed  Google Scholar 

  3. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are MicroRNA targets. Cell. 2005;120(1):15–20.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med. 2009;361(15):1437–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bader AG. miR-34-a microRNA replacement therapy is headed to the clinic. Front Genet. 2012;3:120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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(17):4780–91.

    Article  CAS  PubMed  Google Scholar 

  8. Li W, Xie L, He X, Li J, Tu K, Wei L, et al. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma. Int J Cancer. 2008;123(7):1616–22.

    Article  CAS  PubMed  Google Scholar 

  9. Sato F, Hatano E, Kitamura K, Myomoto A, Fujiwara T, Takizawa S, et al. MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the Milan criteria. PLoS One. 2011;6(1):e16435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shih TC, Tien YJ, Wen CJ, Yeh TS, Yu MC, Huang CH, et al. MicroRNA-214 downregulation contributes to tumor angiogenesis by inducing secretion of the hepatoma-derived growth factor in human hepatoma. J Hepatol. 2012;57(3):584–91.

    Article  CAS  PubMed  Google Scholar 

  11. Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A, Cabellos L, Minguez B, et al. MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology. 2011;140(5):1618–28.e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Roessler S, Jia HL, Budhu A, Forgues M, Ye QH, Lee JS, et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res. 2010;70(24):10202–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Agrawal T, Gupta GK, Agrawal DK. Calcitriol decreases expression of importin alpha3 and attenuates RelA translocation in human bronchial smooth muscle cells. J Clin Immunol. 2012;32(5):1093–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sun X, Icli B, Wara AK, Belkin N, He S, Kobzik L, et al. MicroRNA-181b regulates NF-kappaB-mediated vascular inflammation. J Clin Invest. 2012;122(6):1973–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang N, Ekanem NR, Sakyi CA, Ray SD. Hepatocellular carcinoma and microRNA: new perspectives on therapeutics and diagnostics. Adv Drug Deliv Rev. 2015;81:62–74. doi:10.1016/j.addr.2014.10.029 %/Copyright (c) 2014 Elsevier B.V. All rights reserved.

    Article  CAS  PubMed  Google Scholar 

  16. Qiu G, Lin Y, Zhang H, Wu D. miR-139-5p inhibits epithelial-mesenchymal transition, migration and invasion of hepatocellular carcinoma cells by targeting ZEB1 and ZEB2. Biochem Biophys Res Commun. 2015;463(3):315–21.

    Article  CAS  PubMed  Google Scholar 

  17. Wu L, Cai C, Wang X, Liu M, Li X, Tang H. MicroRNA-142-3p, a new regulator of RAC1, suppresses the migration and invasion of hepatocellular carcinoma cells. FEBS Lett. 2011;585(9):1322–30.

    Article  CAS  PubMed  Google Scholar 

  18. Bae HJ, Noh JH, Kim JK, Eun JW, Jung KH, Kim MG, et al. MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma. Oncogene. 2014;33(20):2557–67.

    Article  CAS  PubMed  Google Scholar 

  19. Kim HS, Lee KS, Bae HJ, Eun JW, Shen Q, Park SJ, et al. MicroRNA-31 functions as a tumor suppressor by regulating cell cycle and epithelial-mesenchymal transition regulatory proteins in liver cancer. Oncotarget. 2015;6(10):8089–102.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Liu Z, Tu K, Liu Q. Effects of microRNA-30a on migration, invasion and prognosis of hepatocellular carcinoma. FEBS Lett. 2014;588(17):3089–97.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang J, Yang Y, Yang T, Yuan S, Wang R, Pan Z, et al. Double-negative feedback loop between microRNA-422a and forkhead box (FOX)G1/Q1/E1 regulates hepatocellular carcinoma tumor growth and metastasis. Hepatology. 2015;61(2):561–73.

    Article  CAS  PubMed  Google Scholar 

  22. Tryndyak VP, Ross SA, Beland FA, Pogribny IP. Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet. Mol Carcinog. 2009;48(6):479–87.

    Article  CAS  PubMed  Google Scholar 

  23. Hernandez JM, Elahi A, Clark CW, Wang J, Humphries LA, Centeno B, et al. miR-675 mediates downregulation of Twist1 and Rb in AFP-secreting hepatocellular carcinoma. Ann Surg Oncol. 2013;20(Suppl 3):S625–35.

    Article  PubMed  Google Scholar 

  24. Zhang S, Zhang H, Zhu J, Zhang X, Liu Y. MiR-522 contributes to cell proliferation of human glioblastoma cells by suppressing PHLPP1 expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2015;70:164–9.

    Article  Google Scholar 

  25. Zhang ZL, Bai ZH, Wang XB, Bai L, Miao F, Pei HH. miR-186 and 326 predict the prognosis of pancreatic ductal adenocarcinoma and affect the proliferation and migration of cancer cells. PLoS One. 2015;10(3):e0118814.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Song M, Yin Y, Zhang J, Zhang B, Bian Z, Quan C, et al. MiR-139-5p inhibits migration and invasion of colorectal cancer by downregulating AMFR and NOTCH1. Protein Cell. 2014;5(11):851–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sun C, Sang M, Li S, Sun X, Yang C, Xi Y, et al. Hsa-miR-139-5p inhibits proliferation and causes apoptosis associated with down-regulation of c-met. Oncotarget. 2015;6(37):39756–92.

    PubMed  PubMed Central  Google Scholar 

  28. Zhang HD, Sun DW, Mao L, Zhang J, Jiang LH, Li J, et al. MiR-139-5p inhibits the biological function of breast cancer cells by targeting Notch1 and mediates chemosensitivity to docetaxel. Biochem Biophys Res Commun. 2015;465(4):702–13.

    Article  CAS  PubMed  Google Scholar 

  29. Xu W, Hang M, Yuan CY, Wu FL, Chen SB, Xue K. MicroRNA-139-5p inhibits cell proliferation and invasion by targeting insulin-like growth factor 1 receptor in human non-small cell lung cancer. Int J Clin Exp Pathol. 2015;8(4):3864–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Duz MB, Karatas OF, Guzel E, Turgut NF, Yilmaz M, Creighton CJ et al. Identification of miR-139-5p as a saliva biomarker for tongue squamous cell carcinoma: a pilot study. Cell Oncol (Dordr). 2016;39(2):187–93.

  31. Cazzoli R, Buttitta F, Di Nicola M, Malatesta S, Marchetti A, Rom WN, et al. microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer. J Thorac Oncol. 2013;8(9):1156–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mi L, Chen Y, Zheng X, Li Y, Zhang Q, Mo D, et al. MicroRNA-139-5p suppresses 3T3-L1 Preadipocyte differentiation through notch and IRS1/PI3K/Akt insulin signaling pathways. J Cell Biochem. 2015;116(7):1195–204.

    Article  CAS  PubMed  Google Scholar 

  33. Maoa R, Zou F, Yang L, Lin S, Li Y, Ma M, et al. The loss of MiR-139-5p promotes colitis-associated tumorigenesis by mediating PI3K/AKT/Wnt signaling. Int J Biochem Cell Biol. 2015;69:153–61.

    Article  PubMed  Google Scholar 

  34. Papangeli I, Kim J, Maier I, Park S, Lee A, Kang Y, et al. MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation. Nat Commun. 2016;7:11268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank all the colleagues in our laboratory for their suggestion and encouragement. The first author is particularly grateful to Yang Hu, a graduate of Kent State University, for her language assistance. The study was supported by the Natural Science Foundation of China (No. 81172350).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Honggang Yu.

Ethics declarations

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Z., Ding, Q., Li, Y. et al. Reanalysis of microRNA expression profiles identifies novel biomarkers for hepatocellular carcinoma prognosis. Tumor Biol. 37, 14779–14787 (2016). https://doi.org/10.1007/s13277-016-5369-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5369-3

Keywords

Navigation