Abstract
Hereditary Tyrosinemia type 1 (HT1) is a metabolic liver disease caused by genetic defects of fumarylacetoacetate hydrolase (FAH), an enzyme necessary to complete the breakdown of tyrosine. The severe hepatic dysfunction caused by the lack of this enzyme is prevented by the therapeutic use of NTBC (2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione). However despite the treatment, chronic hepatopathy and development of hepatocellular carcinoma (HCC) are still observed in some HT1 patients. Growing evidence show the important role of heat shock proteins (HSPs) in many cellular processes and their involvement in pathological diseases including cancer. Their survival-promoting effect by modulation of the apoptotic machinery is often correlated with poor prognosis and resistance to therapy in a number of cancers. Here, we sought to gain insight into the pathophysiological mechanisms associated with liver dysfunction and tumor development in a murine model of HT1. Differential gene expression patterns in livers of mice under HT1 stress, induced by drug retrieval, have shown deregulation of stress and cell death resistance genes. Among them, genes coding for HSPB and HSPA members, and for anti-apoptotic BCL-2 related mitochondrial proteins were associated with the hepatocarcinogenetic process. Our data highlight the variation of stress pathways related to HT1 hepatocarcinogenesis suggesting the role of HSPs in rendering tyrosinemia-affected liver susceptible to the development of HCC.
Highlights
Molecular chaperones play a key role as regulators of the apoptotic process [1]
We investigated the different expression patterns of heat shock proteins (HSPs) and other anti-apoptotic proteins in liver cell transformation during hepatocarcinogenesis in a murine model of hereditary tyrosinemia type 1 (HT1)
Our previous studies demonstrate the changes in the activation state of cellular signaling pathways in response to Hereditary Tyrosinemia type 1 (HT1) stress that have been observed after one to five weeks of NTBC withdrawal [30]
Summary
Molecular chaperones play a key role as regulators of the apoptotic process [1]. Clinical data have demonstrated a correlation between increased HSPs expression and invasive potential of tumors [2,3]. 4-hydroxyphenylpyruvate dioxygenase (HPPD), one of the enzymes involved in the catabolic pathway upstream of FAH, and prevents the formation of toxic products responsible for liver damage (Figure 1). The efficacy of this therapy has improved the liver disease associated with FAH deficiency. Our previous studies showed that the HT1 phenotype induced by NTBC-withdrawal causes a cellular insult eliciting the ER stress response and increasing the level of stress-related proteins [29] This hepatic stress causes the activation of many survival pathways and inhibits the intrinsic apoptotic cascade promoting hepatocarcinogenesis [30]. Molecular chaperones have multiple roles in cell survival, that depend on their distinctive features, one of them being their interactions with anti-apoptotic proteins of the BAG and BCL-2 families [31]
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