The Molecular Chaperone HSP70 Controls Liver Cancer Initiation and Progression by Regulating Adaptive DNA-Damage and MAPK/ERK Signaling Pathways

ABSTRACT

Delineating the mechanisms that drive hepatic injury and hepatocellular carcinoma (HCC) progression is critical for development of novel treatments for recurrent and advanced HCC, but also diagnostic and preventive strategies. Heat shock protein 70 (HSP70) acts in concert with several co-chaperones and nucleotide exchange factors and plays an essential role in protein quality control that increases survival by protecting cells against environmental stressors. Specifically, HSP70-mediated response has been implicated in the pathogenesis of cancer, but the specific mechanisms by which HSP70 may support malignant cell transformation remains to be fully elucidated. Here, we show that genetic ablation of HSP70 markedly impairs HCC initiation and progression by distinct but overlapping pathways. This includes the potentiation of carcinogen-induced DNA damage response, at tumor initiation stage, to increase the p53-dependent surveillance response leading to the cell cycle exit or death of genomically damaged differentiated pericentral hepatocytes, and may also prevent their conversion into more proliferating HCC progenitor cells. Subsequently activation of a MAPK/ERK negative feedback pathway diminishes oncogenic signals thereby attenuating pre-malignant cell transformation and tumor progression. Modulation of HSP70 function may be a strategy for interfering with oncogenic signals driving liver cell transformation and tumor progression, thus providing an opportunity for human cancer control.