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MiR-122/Cyclin G1 Interaction Modulates p53 Activity and Affects Doxorubicin Sensitivity of Human Hepatocarcinoma Cells

¹ Dipartimento di Medicina Clinica e CRBA, Policlinico S.Orsola-Malpighi; ² Dipartimento di Chirurgia e dei Trapianti and ³ Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Bologna, Italy; ⁴ Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy; ⁵ Department of Experimental Therapeutics, University of Texas, Houston, Texas; and ⁶ Comprehensive Cancer Center, Ohio State University, Columbus, Ohio

Requests for reprints: Laura Gramantieri, Policlinico S. Orsola-Malpighi, via Albertoni 15, 40138, Bologna, Italy. Phone: 39-051-6364903; Fax: 39-051-6363902; E-mail: laura.gramantieri{at}aosp.bo.it or Massimo Negrini, Università di Ferrara, via L. Borsari 46, 44100 Ferrara, Italy. E-mail: ngm{at}unife.it.

Key Words: microRNA • cyclin G1 • HCC • TTR

The identification of target genes is a key step for assessing the role of aberrantly expressed microRNAs (miRNA) in human cancer and for the further development of miRNA-based gene therapy. MiR-122 is a liver-specific miRNA accounting for 70% of the total miRNA population. Its down-regulation is a common feature of both human and mouse hepatocellular carcinoma (HCC). We have previously shown that miR-122 can regulate the expression of cyclin G1, whose high levels have been reported in several human cancers. We evaluated the role of miR-122 and cyclin G1 expression in hepatocarcinogenesis and in response to treatment with doxorubicin and their relevance on survival and time to recurrence (TTR) of HCC patients. We proved that, by modulating cyclin G1, miR-122 influences p53 protein stability and transcriptional activity and reduces invasion capability of HCC-derived cell lines. In addition, in a therapeutic perspective, we assayed the effects of a restored miR-122 expression in triggering doxorubicin-induced apoptosis and we proved that miR-122, as well as cyclin G1 silencing, increases sensitivity to doxorubicin challenge. In patients resected for HCC, lower miR-122 levels were associated with a shorter TTR, whereas higher cyclin G1 expression was related to a lower survival, suggesting that miR-122 might represent an effective molecular target for HCC. Our findings establish a basis toward the development of combined chemo- and miRNA-based therapy for HCC treatment. [Cancer Res 2009;69(14):5761–7]

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