SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets

Stefania Cannito, Beatrice Foglia, Gianmarco Villano, Cristian Turato, Teresa C Delgado, Elisabetta Morello, Fabrizio Pin, Erica Novo, Lucia Napione, Santina Quarta, Mariagrazia Ruvoletto, Silvano Fasolato, Giacomo Zanus, Sebastiano Colombatto, Fernando Lopitz-Otsoa, David Fernández-Ramos, Federico Bussolino, Salvatore Sutti, Emanuele Albano, Maria Luz Martínez-ChantarPatrizia Pontisso, Maurizio Parola

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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.

Original languageEnglish
JournalCancers
Volume11
Issue number12
DOIs
Publication statusPublished - Dec 4 2019

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    Cannito, S., Foglia, B., Villano, G., Turato, C., Delgado, T. C., Morello, E., Pin, F., Novo, E., Napione, L., Quarta, S., Ruvoletto, M., Fasolato, S., Zanus, G., Colombatto, S., Lopitz-Otsoa, F., Fernández-Ramos, D., Bussolino, F., Sutti, S., Albano, E., ... Parola, M. (2019). SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets. Cancers, 11(12). https://doi.org/10.3390/cancers11121933