TY - JOUR
T1 - MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells
AU - Fornari, Francesca
AU - Gramantieri, Laura
AU - Giovannini, Catia
AU - Veronese, Angelo
AU - Ferracin, Manuela
AU - Sabbioni, Silvia
AU - Calin, George Adrian
AU - Grazi, Gian Luca
AU - Croce, Carlo Maria
AU - Tavolari, Simona
AU - Chieco, Pasquale
AU - Negrini, Massimo
AU - Bolondi, Luigi
PY - 2009/7/15
Y1 - 2009/7/15
N2 - 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 G1s ilencing, increases sensitivity to doxorubicin challenge. In patients resected for HCC, lower miR-122 levels were associated with a shorter TTR, whereas higher cyclin G1expr ession 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.
AB - 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 G1s ilencing, increases sensitivity to doxorubicin challenge. In patients resected for HCC, lower miR-122 levels were associated with a shorter TTR, whereas higher cyclin G1expr ession 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.
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U2 - 10.1158/0008-5472.CAN-08-4797
DO - 10.1158/0008-5472.CAN-08-4797
M3 - Article
C2 - 19584283
AN - SCOPUS:67651007766
VL - 69
SP - 5761
EP - 5767
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 14
ER -