Constitutive and Induced Expression of Heat Shock Proteins During Liver Carcinogenesis and in Hepatomas

Abstract

Exposure of cells to heat or other stresses¹ induces in the chromosomes the appearance of a new set of puffs² and causes changes in gene structure and regulation that finally lead to the activation of synthesis of a distinct group of proteins. These proteins, known historically as heat-shock proteins (hsps), are now often referred to as stress proteins^3–5. The best evolutionarily conserved heat-shock protein, hsp 70, is coded by a multigene family whose members respond in different ways to temperature and are subject to different regulatory mechanisms; the heat-inducible and constitutive proteins have sometimes been confused⁴ At least one of the members of the hsp 70 group is also growth-regulated^6–7 and the activity of the corresponding gene is induced by viral and cellular oncogenes^8,10. In previous studies we have examined the synthesis of hsp in injured liver cells¹¹ and in some hepatomas of different growth rates¹², and have shown that in these tumours hsp 89 and hsp 70 are expressed constitutively, while induction by heat, at least in the case of hsp 70, is progressively reduced from the slow to the fast-growing hepatomas¹³. Later on we became aware of the fact that hsc 73, the major heat-shock related protein, rather than hsp 70 itself, is the main constitutively synthesized protein in unstressed cells; moreover recent data showed that hsc 73 is expressed at higher level in transformed cells than in their non-transformed counterparts¹⁴. In the present paper we report the results of an investigation with a probe for hsc 73, which became recently available to us, on the constitutive expression of hsc 73 gene in liver cells submitted to a multistep carcinogenic treatment and in transplantable hepatomas, both solid and in ascitic form, of various growth rates. The main purpose of the investigation was to see if the constitutive expression of hsc 73 is an event occurring during the carcinogenic treatment, presumably associated with initiation and/or promotion, or a relatively late outcome during the growth of the established tumour, presumably associated with tumor progression.