title: SerpinB3 and Yap Interplay Increases Myc Oncogenic Activity.
abstract: SerpinB3 has been recently described as an early marker of liver carcinogenesis, but the potential mechanistic role of this serpin in tumor development is still poorly understood. Overexpression of Myc often correlates with more aggressive tumour forms, supporting its involvement in carcinogenesis. Yes-associated protein (Yap), the main effector of the Hippo pathway, is a central regulator of proliferation and it has been found up-regulated in hepatocellular carcinomas. The study has been designed to investigate and characterize the interplay and functional modulation of Myc by SerpinB3 in liver cancer. Results from this study indicate that Myc was up-regulated by SerpinB3 through calpain and Hippo-dependent molecular mechanisms in transgenic mice and hepatoma cells overexpressing human SerpinB3, and also in human hepatocellular carcinomas. Human recombinant SerpinB3 was capable to inhibit the activity of Calpain in vitro, likely reducing its ability to cleave Myc in its non oncogenic Myc-nick cytoplasmic form. SerpinB3 indirectly increased the transcription of Myc through the induction of Yap pathway. These findings provide for the first time evidence that SerpinB3 can improve the production of Myc through direct and indirect mechanisms that include the inhibition of generation of its cytoplasmic form and the activation of Yap pathway.
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Turato
authors.affiliation: Dept. of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Cannito
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Simonato
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Villano
authors.affiliation: Dept. of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Morello
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Terrin
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Santina
authors.initials: S
authors.lastname: Quarta
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Biasiolo
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Ruvoletto
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Martini
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Fasolato
authors.affiliation: Unit of Hepatobiliary Surgery and Liver Transplantation, University of Padova, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Zanus
authors.affiliation: Unit of Hepatobiliary Surgery and Liver Transplantation, University of Padova, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Cillo
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Gatta
authors.affiliation: Dept. of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
authors.affiliation: Dept. of Medicine, University of Padova, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pontisso
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D002154:Calpain / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D015843:Serpins / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; C489427:MYC protein, human; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D015843:Serpins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C051072:squamous cell carcinoma-related antigen; D002154:Calpain