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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background: SerpinB3 (SB3) is a hypoxia and hypoxia-inducible factor (HIF)-2α-dependent cysteine-protease inhibitor up-regulated in hepatocellular carcinoma (HCC), released by cancer cells and able to stimulate proliferation and epithelial-to-mesenchymal-transition. Methods: In the study we employed transgenic and knock out SerpinB3 mice, liver cancer cell line, human HCC specimens, and mice receiving diethyl-nitrosamine (DEN) administration plus choline-deficient L-amino acid refined (CDAA) diet (DEN/CDAA protocol). Results: We provide detailed and mechanistic evidence that SB3 can act as a paracrine mediator able to affect the behavior of surrounding cells by differentially up-regulating, in normoxic conditions, HIF-1α and HIF-2α. SB3 acts by (i) up-regulating HIF-1α transcription, facilitating cell survival in a harsh microenvironment and promoting angiogenesis, (ii) increasing HIF-2α stabilization via direct/selective NEDDylation, promoting proliferation of liver cancer cells, and favoring HCC progression. Moreover (iii) the highest levels of NEDD8-E1 activating enzyme (NAE1) mRNA were detected in a subclass of HCC patients expressing the highest levels of HIF-2α transcripts; (iv) mice undergoing DEN/CDAA carcinogenic protocol showed a positive correlation between SB3 and HIF-2α transcripts with the highest levels of NAE1 mRNA detected in nodules expressing the highest levels of HIF-2α transcripts. Conclusions: These data outline either HIF-2α and NEDDylation as two novel putative therapeutic targets to interfere with the procarcinogenic role of SerpinB3 in the development of HCC.

Details

Title
SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors-1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets
Author
Cannito, Stefania 1   VIAFID ORCID Logo  ; Foglia, Beatrice 1   VIAFID ORCID Logo  ; Villano, Gianmarco 2 ; Turato, Cristian 3   VIAFID ORCID Logo  ; Delgado, Teresa C 4   VIAFID ORCID Logo  ; Morello, Elisabetta 1 ; Pin, Fabrizio 1 ; Novo, Erica 1 ; Napione, Lucia 5   VIAFID ORCID Logo  ; Quarta, Santina 6   VIAFID ORCID Logo  ; Ruvoletto, Mariagrazia 2   VIAFID ORCID Logo  ; Fasolato, Silvano 2   VIAFID ORCID Logo  ; Zanus, Giacomo 7 ; Colombatto, Sebastiano 8 ; Fernando Lopitz-Otsoa 4 ; Fernández-Ramos, David 4 ; Bussolino, Federico 9 ; Sutti, Salvatore 10   VIAFID ORCID Logo  ; Albano, Emanuele 10   VIAFID ORCID Logo  ; Maria Luz Martínez-Chantar 4 ; Pontisso, Patrizia 6 ; Parola, Maurizio 1   VIAFID ORCID Logo 

 Department of Clinical and Biological Sciences, Unit of Experimental Medicine & Clinical Pathology, University of Torino, 10125 Torino, Italy; [email protected] (S.C.); [email protected] (B.F.); [email protected] (E.M.); [email protected] (F.P.); [email protected] (E.N.) 
 Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; [email protected] (G.V.); [email protected] (M.R.); [email protected] (S.F.) 
 Veneto Institute of Oncology IOV—IRCCS, 35128 Padova, Italy; [email protected] 
 Liver Disease and Metabolism Laboratory, CIC bioGUNE, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain; [email protected] (T.C.D.); [email protected] (F.L.-O.); [email protected] (D.F.-R.); [email protected] (M.L.M.-C.) 
 Department of Applied Science and Technology, Politecnico di Torino, 10129 Torino, Italy; [email protected]; Laboratory of Vascular Oncology Candiolo Cancer Institute—FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, Italy; [email protected] 
 Department of Medicine, University of Padova, 35128 Padova, Italy; [email protected] (S.Q.); [email protected] (P.P.) 
 Hepatobiliary Surgery, University of Padova, 35128 Padova, Italy; [email protected] 
 Department of Oncology, University of Torino, 10125 Torino, Italy; [email protected] 
 Laboratory of Vascular Oncology Candiolo Cancer Institute—FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, Italy; [email protected]; Department of Oncology, University of Torino, 10125 Torino, Italy; [email protected] 
10  Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University Amedeo Avogadro of East Piedmont, 28100 Novara, Italy; [email protected] (S.S.); [email protected] (E.A.) 
First page
1933
Publication year
2019
Publication date
2019
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2547570150
Copyright
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.