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MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma

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Abstract

The identification of target mRNAs is a key step for assessing the role of aberrantly expressed microRNAs in human cancer. MiR-221 is upregulated in human hepatocellular carcinoma (HCC) as well as in other malignancies. One proven target of miR-221 is CDKN1B/p27, whose downregulation affects HCC prognosis. Here, we proved that the cyclin-dependent kinase inhibitor (CDKI) CDKN1C/p57 is also a direct target of miR-221. Indeed, downregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to miR-221 transfection into HCC-derived cells and a significant upregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to antimiR-221 transfection. A direct interaction of miR-221 with a target site on the 3′ UTR of CDKN1C/p57 mRNA was also demonstrated. By controlling these two CDKIs, upregulation of miR-221 can promote growth of HCC cells by increasing the number of cells in S-phase. To assess the relevance of these studies in primary tumors, matched HCC and cirrhosis samples were assayed for miR-221, for CDKN1B/p27 and CDKN1C/p57 expression. MiR-221 was upregulated in 71% of HCCs, whereas CDKN1B/p27 and CDKN1C/p57 proteins were downregulated in 77% of cases. A significant inverse correlation between miR-221 and both CDKN1B/p27 and CDKN1C/p57 was found in HCCs. In conclusion, we suggest that miR-221 has an oncogenic function in hepatocarcinogenesis by targeting CDKN1B/p27 and CDKN1C/p57, hence promoting proliferation by controlling cell-cycle inhibitors. These findings establish a basis toward the development of therapeutic strategies aimed at blocking miR-221 in HCC.

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Acknowledgements

This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC regional grant), by grants from Italian Ministero dell'Università e della Ricerca Scientifica and from Italian Ministero della Salute to MN; by Associazione Italiana per la Ricerca sul Cancro (AIRC regional grant) and Fondazione CARISBO to LB and by Program Project Grants from the National Cancer Institute to CMC and by a Kimmel Foundation Scholar award to GAC. FF is a recipient of a fellowship from Associazione Italiana per la Ricerca sul Cancro (AIRC) and MF is a recipient of a fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC).

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Authors and Affiliations

  1. Dipartimento di Medicina Interna e Gastroenterologia e Centro di Ricerca Biomedica Applicata, Università di Bologna, Policlinico S Orsola, Bologna, Italy

    F Fornari, L Gramantieri, C Giovannini & L Bolondi

  2. Dipartimento di Medicina Sperimentale e Diagnostica e Centro Interdipartimentale per la Ricerca sul Cancro, Università di Ferrara, Ferrara, Italy

    M Ferracin, A Veronese, S Sabbioni, C M Croce & M Negrini

  3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G A Calin

  4. Dipartimento di Chirurgia e dei Trapianti, Università di Bologna, Policlinico S Orsola, Bologna, Italy

    G L Grazi

  5. Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    C M Croce

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  1. F Fornari
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  2. L Gramantieri
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  3. M Ferracin
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  4. A Veronese
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  5. S Sabbioni
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  6. G A Calin
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  7. G L Grazi
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  8. C Giovannini
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  9. C M Croce
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  10. L Bolondi
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  11. M Negrini
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Correspondence to L Gramantieri or M Negrini.

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Fornari, F., Gramantieri, L., Ferracin, M. et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 27, 5651–5661 (2008). https://doi.org/10.1038/onc.2008.178

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  • DOI: https://doi.org/10.1038/onc.2008.178

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