Suppression of p53 by Notch3 is mediated by Cyclin G1 and sustained by MDM2 and miR-221 axis in hepatocellular carcinoma

Catia Giovannini; Manuela Minguzzi; Michele Baglioni; Francesca Fornari; Ferdinando Giannone; Matteo Ravaioli; Matteo Cescon; Pasquale Chieco; Luigi Bolondi; Laura Gramantieri

doi:10.18632/oncotarget.2523

Suppression of p53 by Notch3 is mediated by Cyclin G1 and sustained by MDM2 and miR-221 axis in hepatocellular carcinoma

Oncotarget. 2014 Nov 15;5(21):10607-20. doi: 10.18632/oncotarget.2523.

Affiliations

¹ Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, Bologna, Italy. Department of Medical and Surgical Sciences University of Bologna, Bologna, Italy.
² Department of Medical and Surgical Sciences, General and Transplant Surgery Unit, University of Bologna, Bologna, Italy.
³ Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, Bologna, Italy.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Blotting, Western
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / pathology
Cell Cycle
Cell Movement
Cell Proliferation
Cyclin G1 / antagonists & inhibitors
Cyclin G1 / genetics
Cyclin G1 / metabolism*
Flow Cytometry
Gene Expression Regulation, Neoplastic
Humans
Immunoenzyme Techniques
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Male
MicroRNAs / genetics*
Mutation / genetics
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism*
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Rats
Rats, Wistar
Real-Time Polymerase Chain Reaction
Receptor, Notch3
Receptors, Notch / antagonists & inhibitors
Receptors, Notch / genetics
Receptors, Notch / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / antagonists & inhibitors*
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Xenograft Model Antitumor Assays

Substances

CCNG1 protein, human
Cyclin G1
MIRN221 microRNA, human
MicroRNAs
NOTCH3 protein, human
RNA, Messenger
RNA, Small Interfering
Receptor, Notch3
Receptors, Notch
TP53 protein, human
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2