OVEREXPRESSION OF GLUCOSE-6-PHOSPHATE-DEHYDROGENASE IN RAT HEPATIC PRENEOPLASIA AND NEOPLASIA

Abstract

Abundance of messenger RNA (mRNA) and activity of glucose-6-phosphate dehydrogenase (G6PDH), the rate limiting enzyme of the oxidative pentose phosphate pathway, were studied in preneoplastic foci of altered hepatocytes (FAH) and hepatocellular carcinomas (HCC) induced in rats by limited oral exposure to N-nitrosomorpholine (NNM-stop model). Northern blot analysis revealed increased amounts of G6PDH-mRNA in 9/10 HCC, which are apparently not due to structural alterations of the G6PDH gene as studied by Southern blot analysis. In four additional HCC elevated expression of G6PDH was demonstrated by in situ hybridization to antisense-mRNA and by catalytic enzyme histochemistry. This correlative molecular genetic and enzyme histochemical approach was also used to study G6PDH expression in FAH of different phenotypes, namely glycogen storage foci (GSF), mixed cell foci (MCF) acid basophilic cell foci (BCF), representing early (GSF) and advanced (MCF, BCF) stages of hepatic preneoplasia. mRNA level and activity of G6PDH were closely correlated in all types of lesions and increased from GSF to MCF/BCF and HCC. These results suggest a predominantly transcriptional regulation of the increasing expression of G6PDH during hepatocarcinogenesis in the rat.