Insulin receptor substrate-1 is over-expressed in glycogenotic but not in amphophilic preneoplastic hepatic foci induced in rats by N-nitrosomorpholine and dehydroepiandrosterone

Cancer Lett. 1999 Jun 1;140(1-2):75-9. doi: 10.1016/s0304-3835(99)00095-6.


Insulin receptor substrate-1 (IRS-1) is over-expressed in preneoplastic glycogenotic hepatic foci (GSF) and is gradually down-regulated during progression of these lesions, via mixed cell foci (MCF), to the basophilic neoplastic phenotype. The aim of the present study was to investigate the effect of dehydroepiandrosterone (DHEA), a weak hepatocarcinogen and tumour enhancer, on IRS-1 expression. Hepatocellular lesions were induced by N-nitrosomorpholine followed by DHEA. Under these conditions, many glycogen-poor amphophilic (APF) and intermediate cell foci (ICF) appear, in addition to GSF and MCF. IRS-1 was over-expressed in 215 out of 295 GSF, in 50 out of 53 MCF and in a glycogen-rich mixed cell adenoma. IRS-1 expression was not shown in 147 APF, 51 ICF and 5 amphophilic hepatocellular adenomas, and 3 out of 5 hepatocellular carcinomas showed a weak IRS-1 expression. The results suggest a close association of IRS-1 over-expression with the glycogenotic hepatocellular phenotype. The modulation and enhancement of tumour progression by DHEA is associated with a shift from glycogenosis to amphophilia and basophilia, and a down-regulation of IRS-1 expression.

MeSH terms

  • Adenoma, Liver Cell / chemically induced
  • Adenoma, Liver Cell / metabolism*
  • Animals
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / metabolism*
  • Dehydroepiandrosterone
  • Female
  • Glycogen / metabolism*
  • Immunohistochemistry
  • Insulin Receptor Substrate Proteins
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / metabolism*
  • Nitrosamines
  • Phosphoproteins / biosynthesis*
  • Precancerous Conditions / metabolism*
  • Rats
  • Rats, Sprague-Dawley


  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Nitrosamines
  • Phosphoproteins
  • N-nitrosomorpholine
  • Dehydroepiandrosterone
  • Glycogen