Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Circulating microRNA-192 as a diagnostic biomarker in human chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is known as the most common lymphoid malignancy in the Western world. MicroRNAs (miRNAs) are a class of small noncoding RNAs with pivotal roles in cellular and molecular processes related to different malignancies including CLL. Recently, some studies have shown that miR-192 plays a key role in CLL pathogenesis through increasing CDKN1A/p21 levels, suppression of Bcl-2 and enhancement of wild-type P53 and cell cycle arrest. Forty samples, including 20 patients with CLL, diagnosed in Omid hospital (Isfahan, Iran) and 20 healthy controls were sampled during a period of 4 months. Using real-time PCR method, expression of miR-192 was analyzed in peripheral blood mononuclear cells (PBMCs) of CLL patients in comparison with healthy subjects. In silico molecular signaling pathway enrichment analysis was also performed on validated and predicted targets (targetome) of miR-192 in DAVID database to explore possible role of miR-192 in some pathways. The expression of miR-192 was found to be significantly reduced (~2.5-folds) in CLL patients compared with healthy subjects (P=0.002). In silico molecular signaling pathway enrichment analysis detected cell indicated signaling pathway as one of the most statistically relevant pathway with miR-192 targetome. Our findings showed that miR-192 could be a biomarker for early diagnosis of CLL.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Chiorazzi N, Rai KR, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med 2005; 352: 804–815.

    Article  CAS  Google Scholar 

  2. Li S, Moffett HF, Lu J, Werner L, Zhang H, Ritz J et al. MicroRNA expression profiling identifies activated B cell status in chronic lymphocytic leukemia cells. PloS One 2011; 6: e16956.

    Article  CAS  Google Scholar 

  3. Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR . Relationship between p53 dysfunction, CD38 expression, andIgV H mutation in chronic lymphocytic leukemia. Blood 2002; 100: 1404–1409.

    Article  CAS  Google Scholar 

  4. Fernando TR, Rodriguez-Malave NI, Rao DS . MicroRNAs in B cell development and malignancy. J Hematol Oncol 2012; 5: 7.

    Article  CAS  Google Scholar 

  5. Moussay E, Wang K, Cho J-H, van Moer K, Pierson S, Paggetti J et al. MicroRNA as biomarkers and regulators in B-cell chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2011; 108: 6573–6578.

    Article  CAS  Google Scholar 

  6. Calin GA, Liu C-G, Sevignani C, Ferracin M, Felli N, Dumitru CD et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci USA 2004; 101: 11755–11760.

    Article  CAS  Google Scholar 

  7. Teimori H, Ashoori S, Akbari MT, Naeini MM, Chaleshtori MH . FISH Analysis for del6q21 and del17p13 in B-cell chronic lymphocytic leukemia in Iranians. Iran Red Crescent Med J 2013; 15: 107.

    Article  Google Scholar 

  8. Zent CS . Time to test CLL p53 function. Blood 2010; 115: 4154–4155.

    Article  CAS  Google Scholar 

  9. Gholamin S, Pasdar A, Sadegh Khorrami M, Mirzaei H, Reza Mirzaei H, Salehi R et al. The potential for circulating microRNAs in the diagnosis of myocardial infarction: a novel approach to disease diagnosis and treatment. Curr Pharm Des 2016; 22: 397–403.

    Article  CAS  Google Scholar 

  10. Mirzaei H, Gholamin S, Shahidsales S, Sahebkar A, Jafaari MR, Mirzaei HR et al. MicroRNAs as potential diagnostic and prognostic biomarkers in melanoma. Eur J Cancer 2016; 53: 25–32.

    Article  CAS  Google Scholar 

  11. Simonian M, Mosallayi M, Mirzaei H . Circulating miR-21 as novel biomarker in gastric cancer: diagnostic and prognostic biomarker. Cancer Res Ther 2016.

  12. Reza Mirzaei H . Circulating microRNAs in hepatocellular carcinoma: potential diagnostic and prognostic biomarkers. Curr Pharm Des. 2016 (e-pub ahead of print.

  13. Salarini R, Sahebkar A, Mirzaei H, Jaafari M, Riahi M, Hadjati J et al. Epi-drugs and Epi-miRs: moving beyond current cancer therapies. Curr Cancer Drug Targets 2015 (e-pub ahead of print).

  14. Bueno MJ, Malumbres M . MicroRNAs and the cell cycle. Biochim Biophys Acta 2011; 1812: 592–601.

    Article  CAS  Google Scholar 

  15. Braun CJ, Zhang X, Savelyeva I, Wolff S, Moll UM, Schepeler T et al. p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest. Cancer Res 2008; 68: 10094–10104.

    Article  CAS  Google Scholar 

  16. Pettitt A, Sherrington P, Cawley J . The effect of p53 dysfunction on purine analogue cytotoxicity in chronic lymphocytic leukaemia. Br J Haematol 1999; 106: 1049–1051.

    Article  CAS  Google Scholar 

  17. Geng L, Chaudhuri A, Talmon G, Wisecarver JL, Are C, Brattain M et al. MicroRNA-192 suppresses liver metastasis of colon cancer. Oncogene 2014; 33: 5332–5340.

    Article  CAS  Google Scholar 

  18. Chen Q, Ge X, Zhang Y, Xia H, Yuan D, Tang Q et al. Plasma miR-122 and miR-192 as potential novel biomarkers for the early detection of distant metastasis of gastric cancer. Oncol Rep 2014; 31: 1863–1870.

    Article  CAS  Google Scholar 

  19. Di Lisio L, Sánchez-Beato M, Gómez-López G, Rodríguez ME, Montes-Moreno S, Mollejo M et al. MicroRNA signatures in B-cell lymphomas. Blood Cancer J 2012; 2: e57.

    Article  CAS  Google Scholar 

  20. Georges SA, Biery MC, Kim S-y, Schelter JM, Guo J, Chang AN et al. Coordinated regulation of cell cycle transcripts by p53-Inducible microRNAs, miR-192 and miR-215. Cancer Res 2008; 68: 10105–10112.

    Article  CAS  Google Scholar 

  21. Negrini M, Cutrona G, Bassi C, Fabris S, Zagatti B, Colombo M et al. microRNAome expression in chronic lymphocytic leukemia: comparison with normal B-cell subsets and correlations with prognostic and clinical parameters. Clin Cancer Res 2014; 20: 4141–4153.

    Article  CAS  Google Scholar 

  22. Xiao F, Zuo Z, Cai G, Kang S, Gao X, Li T . miRecords: an integrated resource for microRNA–target interactions. Nucleic Acids Res 2009; 37: D105–D110.

    Article  CAS  Google Scholar 

  23. Hsu S-D, Lin F-M, Wu W-Y, Liang C, Huang W-C, Chan W-L et al. miRTarBase: a database curates experimentally validated microRNA–target interactions. Nucleic Acids Res 2011; 39: D163–169.

    Article  CAS  Google Scholar 

  24. Huang DW, Sherman BT, Lempicki RA . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4: 44–57.

    Article  CAS  Google Scholar 

  25. Kanehisa M, Goto S . KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000; 28: 27–30.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Decker T, Schneller F, Miething C, Jahn T, Duyster J, Peschel C . Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27. Leukemia. 08876924. 2002; 16: 327–334.

    Article  CAS  Google Scholar 

  28. Leupin N, Cenni B, Novak U, Hügli B, Graber HU, Tobler A et al. Disparate expression of the PTEN gene: a novel finding in B‐cell chronic lymphocytic leukaemia (B‐CLL). Br J Haematol 2003; 121: 97–100.

    Article  CAS  Google Scholar 

  29. Majid A, Tsoulakis O, Walewska R, Gesk S, Siebert R, Kennedy DBJ et al. BCL2 expression in chronic lymphocytic leukemia: lack of association with the BCL2− 938 A> C promoter single nucleotide polymorphism. Blood 2008; 111: 874–877.

    Article  CAS  Google Scholar 

  30. McKeller MR, Robetorye RS, Dahia PL, Aguiar RC . Integrity of the CBL gene in mature B-cell malignancies. Blood 2009; 114: 4321–4322.

    Article  CAS  Google Scholar 

  31. Bernard P, Fleming A, Lacombe A, Harley VR, Vilain E . Wnt4 inhibits β‐catenin/TCF signalling by redirecting β‐catenin to the cell membrane. Biol Cell 2008; 100: 167–177.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by Mansour Salehi (PhD) in Isfahan university of Medical Sciences. We thank all patients who contributed to this investigation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Salehi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Cancer Gene Therapy website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fathullahzadeh, S., Mirzaei, H., Honardoost, M. et al. Circulating microRNA-192 as a diagnostic biomarker in human chronic lymphocytic leukemia. Cancer Gene Ther 23, 327–332 (2016). https://doi.org/10.1038/cgt.2016.34

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2016.34

This article is cited by

Search

Quick links