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

被引:370
作者
Fornari, Francesca [1 ,2 ]
Gramantieri, Laura [1 ,2 ]
Giovannini, Catia [1 ,2 ]
Veronese, Angelo [5 ]
Ferracin, Manuela [5 ]
Sabbioni, Silvia [5 ]
Calin, George Adrian [6 ]
Grazi, Gian Luca [3 ]
Croce, Carlo Maria [5 ,7 ]
Tavolari, Simona [4 ]
Chieco, Pasquale [1 ,2 ]
Negrini, Massimo [5 ]
Bolondi, Luigi [1 ,2 ]
机构
[1] St Orsola Marcello Malpighi Hosp, Dipartimento Med Clin, I-40138 Bologna, Italy
[2] St Orsola Marcello Malpighi Hosp, CRBA, I-40138 Bologna, Italy
[3] Univ Bologna, Dipartimento Chirurg & Trapianti, Bologna, Italy
[4] Univ Bologna, Dipartimento Biol Evoluzionist Sperimentale, Bologna, Italy
[5] Univ Ferrara, Dipartimento Med Sperimentale & Diagnost, I-44100 Ferrara, Italy
[6] Univ Texas Houston, Dept Expt Therapeut, Houston, TX USA
[7] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA
关键词
CYCLIN-G; SUPPRESSOR GENE; HUMAN CANCER; G2/M ARREST; DNA-DAMAGE; IN-VIVO; EXPRESSION; TUMOR; TARGET; MICRORNAS;
D O I
10.1158/0008-5472.CAN-08-4797
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
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):576.-7]
引用
收藏
页码:5761 / 5767
页数:7
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