Insulin-like growth factor I 1 (IGF II) regulated tissue-specific gene expression in hepatoma cell lines, but had no effect on expression of tissue-specific genes in primary cultures of E l 4 and newborn rat liver cells depleted of erythroid cells. No change was observed in these primary cultures with respect to a-fetoprotein (a-FP), albumin, cytokeratin 19 (CKI 9), y-glutamyltranspeptidase (GGT), and IGF I 1 receptors. Two well-differentiated hepatomas, HepG2 and FTO-2B, and a poorly differentiated hepatoma, H, A, C, , did not show increased proliferation in the presence of IGF II, yet showed gene expression changes in response to IGF II.
In HepG2 cells, IGF II increased albumin mRNA levels and resulted in a shift from clusters of cells positive to 100% of the cells expressing immunohistochemically detectable albumin. The transcription factor HNF-3P mRNA and protein levels of the bile duct markers, CK19 and GGT, were also increased in the presence of IGF 11. Other genes tested were not affected, including al-antitrypsin, and two liverspecific transcription factors, HNF-4 and HNF-3a. In FTO-2B cells, IGF II increased the expression of albumin, CK19, and GGT, without accompanying changes in albumin and GGT mRNAs. In H, A, C, cells, IGF II reduced CK19 and OC.3 protein levels and GGT, transferrin, and HNF-3P rnRNAs. The effects of IGF II on H, A, C, cells were not blocked in the presence of an anti-rat IGF I 1 receptor antibody. We conclude that IGF II affects tissue-specific gene expression of hepatomas and qualitative and quantitative aspects of its influence on the hepatomas is dependent on their degree of differentiation. o 1995 Wiley-Liss, Inc.