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

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.

• Authors: Catia Giovannini, Manuela Minguzzi, Michele Baglioni, Francesca Fornari, Ferdinando Giannone, Matteo Ravaioli, Matteo Cescon, Pasquale Chieco, Luigi Bolondi, Laura Gramantieri
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 21 Pg. 10607-20 (Nov 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25431954 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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