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.
Serpin B3 differently up-regulates hypoxia inducible factors -1α and -2α in hepatocellular carcinoma: mechanisms revealing novel potential therapeutic targets / 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.; Fernandez-Ramos, D.; Bussolino, F.; Sutti, S.; Albano, E.; Martinez-Chantar, M. L.; Pontisso, P.; Parola, M.. - In: CANCERS. - ISSN 2072-6694. - ELETTRONICO. - 11:12(2019), p. 1933. [10.3390/cancers11121933]
|Titolo:||Serpin B3 differently up-regulates hypoxia inducible factors -1α and -2α in hepatocellular carcinoma: mechanisms revealing novel potential therapeutic targets|
|Data di pubblicazione:||2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3390/cancers11121933|
|Appare nelle tipologie:||1.1 Articolo in rivista|