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.
Highlights
Liver cancer is the sixth most common tumor and the second most frequent cause of cancer-related mortality worldwide [1, 2]
We showed that c-Myc requires an intact mammalian target of rapamycin pathway in order to exert its oncogenic potential in the liver [12]. mTOR is an evolutionary conserved pathway composed of two distinct complexes, referred to as complex 1 and complex 2 [12, 13]
Aberrant activation of the c-Myc transcription factor due to overexpression, translocation, amplification, and/ or protein stabilization has been detected in multiple tumor types, including Hepatocellular carcinoma (HCC) [4,5,6,7,8]
Summary
Liver cancer is the sixth most common tumor and the second most frequent cause of cancer-related mortality worldwide [1, 2]. New therapeutic strategies should be developed in order to significantly improve the prognosis of HCC patients. For this purpose, the identification of new molecular targets is imperative. The ideal target should be selected based on the fact that its modulation would affect only the survival of cancer cells, while sparing the normal ones. In this regard, one option would be to target cancer driver genes, which actively sustain carcinogenesis and whose inhibition triggers tumor restraint. A feasible alternative would be to target key downstream effectors of driver genes, whose repression would be deleterious for tumor cells
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