Hypoxia up-regulates SERPINB3 through HIF-2α in human liver cancer cells
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Stefania Cannito1,*, Cristian Turato2,*, Claudia Paternostro1, Alessandra Biasiolo2, Sebastiano Colombatto3, Irene Cambieri4, Santina Quarta2, Erica Novo1, Elisabetta Morello1, Gianmarco Villano2, Silvano Fasolato2, Tiziana Musso5, Ezio David6, Ignazia Tusa7, Elisabetta Rovida7, Riccardo Autelli1, Antonina Smedile8, Umberto Cillo9, Patrizia Pontisso2 and Maurizio Parola1
1 Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
2 Department of Medicine, University of Padova, Italy
3 Department of Oncology, University of Torino, Italy
4 Department of Plastic Surgery and Burn Unit Skin Bank, CTO Hospital, Torino, Italy
5 Department of Public Health and Pediatric Sciences, University of Torino, Italy
6 Pathology Unit, San Giovanni Battista Hospital, Torino, Italy
7 Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Firenze, Italy
8 Gastroenterology and Hepatology Division, San Giovanni Battista Hospital, Torino, Italy
9 Unit of Hepatobiliary Surgery and Liver Transplantation, University of Padova, Italy
* These authors contributed equally to this work
Maurizio Parola, email:
Keywords: SERPINB3, hypoxia, hepatocellular carcinoma, HIF-2α, reactive oxygen species
Received: September 01, 2014 Accepted: December 09, 2014 Published: December 10, 2014
SERPINB3 is a cysteine-proteases inhibitor up-regulated in a significant number of cirrhotic patients carrying hepatocellular carcinoma (HCC) and recently proposed as a prognostic marker for HCC early recurrence. SERPINB3 has been reported to stimulate proliferation, inhibit apoptosis and, similar to what reported for hypoxia, to trigger epithelial-to-mesenchymal transition (EMT) and increased invasiveness in liver cancer cells. This study has investigated whether SERPINB3 expression is regulated by hypoxia-related mechanisms in liver cancer cells.
Exposure of HepG2 and Huh7 cells to hypoxia up-regulated SERPINB3 transcription, protein synthesis and release in the extracellular medium. Hypoxia-dependent SERPINB3 up-regulation was selective (no change detected for SERPINB4) and operated through hypoxia inducible factor (HIF)-2α (not HIF-1α) binding to SERPINB3 promoter, as confirmed by chromatin immuno-precipitation assay and silencing experiments employing specific siRNAs. HIF-2α-mediated SERPINB3 up-regulation under hypoxic conditions required intracellular generation of ROS. Immuno-histochemistry (IHC) and transcript analysis, performed in human HCC specimens, revealed co-localization of the two proteins in liver cancer cells and the existence of a positive correlation between HIF-2α and SERPINB3 transcript levels, respectively.
Hypoxia, through HIF-2α-dependent and redox-sensitive mechanisms, up-regulates the transcription, synthesis and release of SERPINB3, a molecule with a high oncogenic potential.
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