Heat shock protein 70 promotes HCC by modulating DNA-damage response, MAPK/ERK signaling and cellular senescence

Abstract

The mechanisms that drive hepatocellular carcinoma (HCC) development are not well understood. Heat shock protein 70 (HSP70) plays a critical role in protein quality control. The HSP70-mediated response has been implicated in the development of different cancer types, however, the detailed mechanisms by which HSP70 supports tumor progression remains to be investigated. In this research work we observed that HSP70 deletion impairs HCC development by modulating the carcinogen-induced DNA damage response. This results in increased sensitivity to p53-dependent apoptosis, activation of MAPK/ERK negative feedback signaling pathway, and induction of cellular senescence. Inactivation of HSP70 may be a strategy to interfere with signaling pathways that drive liver cancer progression thus offering a therapeutic possibility for human HCC treatment. Note: The research data described in this Ph.D. Thesis are not published. Additional experimental work is needed to verify the data and solidify the mechanistic conclusions of this work before we seek publication of the data in a peer reviewed scientific journal. In light of new data generated from additional studies, we may need to modify or revised our mechanistic conclusions.