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

ABSTRACT: BACKGROUND:SerpinB3 (SB3) is a hypoxia and hypoxia-inducible factor (HIF)-2?-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-1? and HIF-2?. SB3 acts by (i) up-regulating HIF-1? transcription, facilitating cell survival in a harsh microenvironment and promoting angiogenesis, (ii) increasing HIF-2? 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-2? transcripts; (iv) mice undergoing DEN/CDAA carcinogenic protocol showed a positive correlation between SB3 and HIF-2? transcripts with the highest levels of NAE1 mRNA detected in nodules expressing the highest levels of HIF-2? transcripts. Conclusions: These data outline either HIF-2? and NEDDylation as two novel putative therapeutic targets to interfere with the procarcinogenic role of SerpinB3 in the development of HCC.

SUBMITTER: Cannito S 

PROVIDER: S-EPMC6966556 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature