Oncotarget

Research Papers:

Inhibition of HSF1 suppresses the growth of hepatocarcinoma cell lines in vitro and AKT-driven hepatocarcinogenesis in mice

Antonio Cigliano, Chunmei Wang, Maria G. Pilo, Marta Szydlowska, Stefania Brozzetti, Gavinella Latte, Giovanni M. Pes, Rosa M. Pascale, Maria A. Seddaiu, Gianpaolo Vidili, Silvia Ribback, Frank Dombrowski, Matthias Evert, Xin Chen and Diego F. Calvisi _

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Oncotarget. 2017; 8:54149-54159. https://doi.org/10.18632/oncotarget.16927

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Abstract

Antonio Cigliano1,*, Chunmei Wang2,*, Maria G. Pilo3, Marta Szydlowska1, Stefania Brozzetti4, Gavinella Latte3, Giovanni M. Pes3, Rosa M. Pascale3, Maria A. Seddaiu3, Gianpaolo Vidili3, Silvia Ribback1, Frank Dombrowski1, Matthias Evert5, Xin Chen2 and Diego F. Calvisi3

1Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany

2Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA

3Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy

4Pietro Valdoni Surgery Department, University of Rome La Sapienza, Rome, Italy

5Institut für Pathologie, Universitätsklinikum Regensburg, Regensburg, Germany

*These authors contributed equally to the work

Correspondence to:

Diego F. Calvisi, email: [email protected]

Xin Chen, email: [email protected].

Keywords: hepatocellular carcinoma, HSF1, signaling pathways

Received: March 06, 2017     Accepted: March 27, 2017     Published: April 07, 2017

ABSTRACT

Upregulation of the heat shock transcription factor 1 (HSF1) has been described as a frequent event in many cancer types, but its oncogenic role in hepatocellular carcinoma (HCC) remains poorly delineated. In the present study, we assessed the function(s) of HSF1 in hepatocarcinogenesis via in vitro and in vivo approaches. In particular, we determined the importance of HSF1 on v-Akt murine thymoma viral oncogene homolog (AKT)-induced liver cancer development in mice. We found that knockdown of HSF1 activity via specific siRNA triggered growth restraint by suppressing cell proliferation and inducing massive cell apoptosis in human HCC cell lines. At the molecular level, HSF1 inhibition was accompanied by downregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade and related metabolic pathways. Most importantly, overexpression of a dominant negative form of HSF1 (HSF1dn) in the mouse liver via hydrodynamic gene delivery led to the inhibition of mouse hepatocarcinogenesis driven by overexpression of AKT. In human liver cancer specimens, we detected that HSF1 is progressively induced from human non-tumorous surrounding livers to HCC, reaching the highest expression in the tumors characterized by the poorest outcome (as defined by the length of patients’ survival). In conclusion, HSF1 is an independent prognostic factor in liver cancer and might represent an innovative therapeutic target in HCC subsets characterized by activation of the AKT/mTOR pathway.


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