Oncotarget

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Deregulated c-Myc requires a functional HSF1 for experimental and human hepatocarcinogenesis

Antonio Cigliano _, Maria G. Pilo, Lei Li, Gavinella Latte, Marta Szydlowska, Maria M. Simile, Panagiotis Paliogiannis, Li Che, Giovanni M. Pes, Giuseppe Palmieri, Maria C. Sini, Antonio Cossu, Alberto Porcu, Gianpaolo Vidili, Maria A. Seddaiu, Rosa M. Pascale, Silvia Ribback, Frank Dombrowski, Xin Chen and Diego F. Calvisi

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Oncotarget. 2017; 8:90638-90650. https://doi.org/10.18632/oncotarget.21469

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Abstract

Antonio Cigliano1,*, Maria G. Pilo2,*, Lei Li3,*, Gavinella Latte2, Marta Szydlowska1, Maria M. Simile2, Panagiotis Paliogiannis2, Li Che4, Giovanni M. Pes2, Giuseppe Palmieri5, Maria C. Sini5, Antonio Cossu6, Alberto Porcu2, Gianpaolo Vidili2, Maria A. Seddaiu2, Rosa M. Pascale2, Silvia Ribback1, Frank Dombrowski1, Xin Chen4 and Diego F. Calvisi2

1 Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany

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

3 School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

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

5 Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy

6 Unit of Pathology, Azienda Ospedaliero Universitaria Sassari, Sassari, Italy

* These Authors contributed equally to the work

Correspondence to:

Diego F. Calvisi, email:

Xin Chen, email:

Keywords: hepatocellular carcinoma, liver cancer, HSF1, c-Myc, signalling pathways

Received: August 31, 2017 Accepted: September 21, 2017 Published: October 03, 2017

Abstract

Deregulated activity of the c-Myc protooncogene is a frequent molecular event underlying mouse and human hepatocarcinogenesis. Nonetheless, the mechanisms sustaining c-Myc oncogenic activity in liver cancer remain scarcely delineated. Recently, we showed that the mammalian target of rapamycin complex 1 (mTORC1) cascade is induced and necessary for c-Myc dependent liver tumor development and progression. Since the heat shock factor 1 (HSF1) transcription factor is a major positive regulator of mTORC1 in the cell, we investigated the functional interaction between HSF1 and c-Myc using in vitro and in vivo approaches. We found that ablation of HSF1 restrains the growth of c-Myc-derived mouse hepatocellular carcinoma (HCC) cell lines, where it induces downregulation of c-Myc levels. Conversely, silencing of c-Myc gene in human and mouse HCC cells led to downregulation of HSF1 expression. Most importantly, overexpression of a dominant negative form of HSF1 (HSF1dn) in the mouse liver via hydrodynamic gene delivery resulted in the complete inhibition of mouse hepatocarcinogenesis driven by overexpression of c-Myc. Altogether, the present results indicate that a functional HSF1 is necessary for c-Myc-driven hepatocarcinogenesis. Consequently, targeting HSF1 might represent a novel and effective therapeutic strategy for the treatment of HCC subsets with activated c-Myc signaling.


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