Hypoxia up-regulates SERPINB3 through HIF-2α in human liver cancer cells

被引：50

作者：

Cannito, Stefania ^{[1
,2
]}

Turato, Cristian ^{[3
]}

Paternostro, Claudia ^{[1
,2
]}

Biasiolo, Alessandra ^{[3
]}

Colombatto, Sebastiano ^{[4
]}

Cambieri, Irene ^{[5
,6
]}

Quarta, Santina ^{[3
]}

Novo, Erica ^{[1
,2
]}

Morello, Elisabetta ^{[1
,2
]}

Villano, Gianmarco ^{[3
]}

Fasolato, Silvano ^{[3
]}

Musso, Tiziana ^{[7
]}

David, Ezio ^{[8
]}

Tusa, Ignazia ^{[9
]}

Rovida, Elisabetta ^{[9
]}

Autelli, Riccardo ^{[1
,2
]}

Smedile, Antonina ^{[10
]}

Cillo, Umberto ^{[11
]}

Pontisso, Patrizia ^{[3
]}

Parola, Maurizio ^{[1
,2
]}

机构：

[1] Univ Turin, Dept Clin & Biol Sci, Unit Expt Med, I-10124 Turin, Italy

[2] Univ Turin, Interuniv Ctr Liver Pathophysiol, I-10124 Turin, Italy

[3] Univ Padua, Dept Med, I-35100 Padua, Italy

[4] Univ Turin, Dept Oncol, I-10124 Turin, Italy

[5] CTO Hosp, Dept Plast Surg, Turin, Italy

[6] CTO Hosp, Burn Unit Skin Bank, Turin, Italy

[7] Univ Turin, Dept Publ Hlth & Pediat Sci, I-10124 Turin, Italy

[8] San Giovanni Battista Hosp, Pathol Unit, Turin, Italy

[9] Univ Florence, Dept Biomed Expt & Clin Sci Mario Serio, I-50121 Florence, Italy

[10] San Giovanni Battista Hosp, Div Gastroenterol & Hepatol, Turin, Italy

[11] Univ Padua, Unit Hepatobiliary Surg & Liver Transplantat, I-35100 Padua, Italy

来源：

ONCOTARGET | 2015年 / 6卷 / 04期

关键词：

SERPINB3; hypoxia; hepatocellular carcinoma; HIF-2; alpha; reactive oxygen species; EPITHELIAL-MESENCHYMAL TRANSITION; INDUCIBLE FACTORS; HEPATOCELLULAR-CARCINOMA; HUMAN TISSUES; STEM-CELLS; EXPRESSION; ANTIGEN; GENE; FACTOR-2-ALPHA; MECHANISMS;

D O I：

10.18632/oncotarget.2943

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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)-2 alpha (not HIF-1 alpha) binding to SERPINB3 promoter, as confirmed by chromatin immuno-precipitation assay and silencing experiments employing specific siRNAs. HIF-2 alpha-mediated SERPINB3 up-regulation under hypoxic conditions required intracellular generation of ROS. Immunohistochemistry (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-2 alpha and SERPINB3 transcript levels, respectively. Hypoxia, through HIF-2 alpha-dependent and redox-sensitive mechanisms, up-regulates the transcription, synthesis and release of SERPINB3, a molecule with a high oncogenic potential.

引用

页码：2206 / 2221

页数：16

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[1] Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection [J].