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.

Deregulated c-Myc requires a functional HSF1 for experimental and human hepatocarcinogenesis / Cigliano, Antonio; Pilo, Maria G.; Li, Lei; Latte, Gavinella; Szydlowska, Marta; Simile, Maria M.; Paliogiannis, Panagiotis; Che, Li; Pes, Giovanni M.; Palmieri, Giuseppe; Sini, Maria C.; Cossu, Antonio; Porcu, Alberto; Vidili, Gianpaolo; Seddaiu, Maria A.; Pascale, Rosa M.; Ribback, Silvia; Dombrowski, Frank; Chen, Xin; Calvisi, Diego F.. - In: ONCOTARGET. - ISSN 1949-2553. - 8:53(2017), pp. 90638-90650. [10.18632/oncotarget.21469]

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

Cigliano, Antonio;Pilo, Maria G.;Latte, Gavinella;Simile, Maria M.;Paliogiannis, Panagiotis;Pes, Giovanni M.;Palmieri, Giuseppe;Sini, Maria C.;Cossu, Antonio
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Porcu, Alberto;Vidili, Gianpaolo;Seddaiu, Maria A.;Pascale, Rosa M.;Calvisi, Diego F.
2017-01-01

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.
2017
Deregulated c-Myc requires a functional HSF1 for experimental and human hepatocarcinogenesis / Cigliano, Antonio; Pilo, Maria G.; Li, Lei; Latte, Gavinella; Szydlowska, Marta; Simile, Maria M.; Paliogiannis, Panagiotis; Che, Li; Pes, Giovanni M.; Palmieri, Giuseppe; Sini, Maria C.; Cossu, Antonio; Porcu, Alberto; Vidili, Gianpaolo; Seddaiu, Maria A.; Pascale, Rosa M.; Ribback, Silvia; Dombrowski, Frank; Chen, Xin; Calvisi, Diego F.. - In: ONCOTARGET. - ISSN 1949-2553. - 8:53(2017), pp. 90638-90650. [10.18632/oncotarget.21469]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/199161
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