Skip to main content
Log in

Clinical significance of miR-221 and its inverse correlation with p27Kip1 in hepatocellular carcinoma

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

The aim of the present study is to explore possible role of miR-221 in the pathogenesis of HCC. Matched HCC and adjacent non-cancerous samples were assayed for the expression of miR-221 and three G1/S transition inhibitors: p27Kip1, p21WAF1/Cip1and TGF-β1 by in situ hybridization and immunohistochemistry respectively. p27Kip1 is one of miR-221’s proven targets. Real time qRT-PCR was used to investigate miR-221 and p27Kip1 transcripts in different clinical stages. Western blotting was used to analyze the expression levels of p27Kip1 protein in different clinical stages. In result, miR-221 and TGF-β1 are frequently up-regulated in HCC, while p27Kip1 and p21WAF1/Cip1 proteins are frequently down-regulated. Moreover, miR-221 and p27Kip1’s expression correlated with metastasis and miR-221’s expression also correlated with tumor size. Both of p21WAF1/Cip1and TGF-β1’s expression correlated with tumor differentiations. miR-221’s upregulation and p27Kip1’s downregulation were significantly associated with tumor stages and metastasis. In conclusion, miR-221 is important in tumorigenesis of HCC, possibly by specifically down-regulating p27Kip1, a cell-cycle inhibitor. These results indicate miR-221 as a new therapeutic target in HCC.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Mazzanti R, Gramantieri L, Bolondi L (2008) Hepatocellular carcinoma: epidemiology and clinical aspects. Mol Aspects Med 29:130–143

    Article  PubMed  Google Scholar 

  2. Edamoto Y, Hara A, Biernat W et al (2003) Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis. Int J Cancer 106:334–341

    Article  PubMed  CAS  Google Scholar 

  3. Schratt GM, Tuebing F, Nigh EA et al (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283–289

    Article  PubMed  CAS  Google Scholar 

  4. Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838

    Article  PubMed  CAS  Google Scholar 

  5. Huang XH, Wang Q, Chen JS et al (2009) Bead-based microarray analysis of microRNA expression in hepatocellular carcinoma: miR-338 is downregulated. Hepatol Res 39:786–794

    Article  PubMed  CAS  Google Scholar 

  6. Visone R, Russo L, Pallante P et al (2007) MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. Endocr Relat Cancer 14:791–798

    Article  PubMed  CAS  Google Scholar 

  7. le Sage C, Nagel R, Egan DA et al (2007) Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J 26:3699–3708

    Article  PubMed  CAS  Google Scholar 

  8. Galardi S, Mercatelli N, Giorda E et al (2007) miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem 282:23716–23724

    Article  PubMed  CAS  Google Scholar 

  9. Fornari F, Gramantieri L, Ferracin M et al (2008) MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 27:5651–5661

    Article  PubMed  CAS  Google Scholar 

  10. Koff A (2006) How to decrease p27Kip1 levels during tumor development. Cancer Cell 9:75–76

    Article  PubMed  CAS  Google Scholar 

  11. Sheahan S, Bellamy CO, Dunbar DR et al (2007) Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFbeta cell cycle arrest. BMC Cancer 7:215

    Article  PubMed  Google Scholar 

  12. Enright AJ, John B, Gaul U et al (2003) MicroRNA targets in Drosophila. Genome Biol 5:R1

    Article  PubMed  Google Scholar 

  13. Krek A, Grun D, Poy MN et al (2005) Combinatorial microRNA target predictions. Nat Genet 37:495–500

    Article  PubMed  CAS  Google Scholar 

  14. Chen JS, Wang Q, Fu XH et al (2009) Involvement of PI3 K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9. Hepatol Res 39:177–186

    Article  PubMed  CAS  Google Scholar 

  15. Chibazakura T, McGrew SG, Cooper JA et al (2004) Regulation of cyclin-dependent kinase activity during mitotic exit and maintenance of genome stability by p21, p27, and p107. Proc Natl Acad Sci USA 101:4465–4470

    Article  PubMed  CAS  Google Scholar 

  16. Benetti A, Berenzi A, Gambarotti M et al (2008) Transforming growth factor-beta1 and CD105 promote the migration of hepatocellular carcinoma-derived endothelium. Cancer Res 68:8626–8634

    Article  PubMed  CAS  Google Scholar 

  17. Yamada Y, Mori H (2003) Pre-cancerous lesions for colorectal cancers in rodents: a new concept. Carcinogenesis 24:1015–1019

    Article  PubMed  CAS  Google Scholar 

  18. Gorgoulis VG, Vassiliou LV, Karakaidos P et al (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:907–913

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (30672053), Chinese Postdoc Foundation (20070410859), The Research Initiation Fund for the Young Teachers of Medical Science of Sun Yat-Sun University(2008005) and Science and Technology Planning Project of Guangdong Province, China (2008B030301036).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Qian Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fu, X., Wang, Q., Chen, J. et al. Clinical significance of miR-221 and its inverse correlation with p27Kip1 in hepatocellular carcinoma. Mol Biol Rep 38, 3029–3035 (2011). https://doi.org/10.1007/s11033-010-9969-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-010-9969-5

Keywords

Navigation