دورية أكاديمية
SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors-1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets
| العنوان: | SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors-1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets |
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| المؤلفون: | Stefania Cannito 1,†, Beatrice Foglia 1,†, Gianmarco Villano 2, Cristian Turato 3, Teresa C Delgado 4, Elisabetta Morello 1, Fabrizio Pin 1, Erica Novo 1, Lucia Napione 5,6, Santina Quarta 7, Mariagrazia Ruvoletto 2, Silvano Fasolato 2, Giacomo Zanus 8, Sebastiano Colombatto 9, Fernando Lopitz-Otsoa 4, David Fernández-Ramos 4, Federico Bussolino 6,9, Salvatore Sutti 10, Emanuele Albano 10, Maria Luz Martínez-Chantar 4, Patrizia Pontisso 7, Maurizio Parola 1,* |
| سنة النشر: | 2019 |
| المجموعة: | Zenodo |
| الوصف: | 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. Keywords: SerpinB3; hypoxia; hypoxia inducible factors HIF-1αand HIF-2α; HCC; NEDD8; NEDDylation |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| العلاقة: | https://zenodo.org/record/4321044Test; https://doi.org/10.5281/zenodo.4321044Test; oai:zenodo.org:4321044 |
| DOI: | 10.5281/zenodo.4321044 |
| الإتاحة: | https://doi.org/10.5281/zenodo.4321044Test https://doi.org/10.5281/zenodo.4321043Test https://zenodo.org/record/4321044Test |
| حقوق: | info:eu-repo/semantics/openAccess ; https://creativecommons.org/licenses/by/4.0/legalcodeTest |
| رقم الانضمام: | edsbas.A31263B0 |
| قاعدة البيانات: | BASE |
| DOI: | 10.5281/zenodo.4321044 |
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