Suppression of p53 by Notch3 is mediated by Cyclin G1 and sustained by MDM2 and miR-221 axis in hepatocellular carcinoma
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Catia Giovannini1,2,*, Manuela Minguzzi1,2,*, Michele Baglioni1,2, Francesca Fornari1,2, Ferdinando Giannone1,2, Matteo Ravaioli3, Matteo Cescon3, Pasquale Chieco1, Luigi Bolondi1,2 and Laura Gramantieri1
1 Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, Bologna, Italy
2 Department of Medical and Surgical Sciences University of Bologna, Bologna, Italy
3 Department of Medical and Surgical Sciences, General and Transplant Surgery Unit, University of Bologna, Bologna, Italy
* These authors contributed equally to this work
Catia Giovannini, email:
Keywords: Notch3, p53, miR-221, CyclinG1, MDM2
Received: June 18, 2014 Accepted: September 24, 2014 Published: September 25, 2014
To successfully target Notch receptors as part of a multidrug anticancer strategy, it will be essential to fully characterize the factors that are modulated by Notch signaling. We recently reported that Notch3 silencing in HCC results in p53 up-regulation in vitro and, therefore, we focused on the mechanisms that associate Notch3 to p53 protein expression. We explored the regulation of p53 by Notch3 signalling in three HCC cell lines HepG2, SNU398 and Hep3B.We found that Notch3 regulates p53 at post-transcriptional level controlling both Cyclin G1 expression and the feed-forward circuit involving p53, miR-221 and MDM2. Moreover, our results were validated in human HCCs and in a rat model of HCC treated with Notch3 siRNAs. Our findings are becoming an exciting area for further in-depth research toward targeted inactivation of Notch3 receptor as a novel therapeutic approach for increasing the drug-sensitivity, and thereby improving the treatment outcome of patients affected by HCC. Indeed, we proved that Notch3 silencing strongly increases the effects of Nutilin-3.With regard to therapeutic implications, Notch3-specific drugs could represent a valuable strategy to limit Notch signaling in the context of hepatocellular carcinoma over-expressing this receptor.
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