Regulation of insulin-like growth factor-II in human liver

Insulin-like growth factors-I and -II (IGF-I and -II) are mitogens in a number of cell types and also have insulin-like actions. IGF-II has an autocrine role in a variety of malignancies; and hypoglycemia is well documented in conditions associated with elevated IGF-II precursor forms in the circulation. The IGFs are modulated by a family of high affinity binding proteins, the IGFBPs. IGF-II precursor forms have a reduced ability to form the ternary complex with IGFBP-3 and the acid labile subunit (ALS) that normally carries IGF-II in the circulation. Most of the biological effects of IGF-II are through the IFG-I-receptor (IGF-IR) and the insulin receptor isoform A (IR-A). The IGF2 gene has a tissue- and development-specific pattern of expression, involving 4 different promoters. Transcripts derived from each promoter give rise to the same translated pro-IGF-II of 156 amino acids, which is sequentially processed into mature IGFII of 67 amino acids. Since the liver is an important site of IGF-II production, the aim of this thesis was to investigate the regulation of hepatic IGF-II. It is shown in human hepatoblastoma, in which IGF-II is often up-regulated, that IR-A is expressed and that there is a down-regulation of IGFBPs that inhibit IGF-II action. This would support an autocrine role for IGF-II in hepatoblastoma. In normal human liver GH had a promoter-specific effect on IGF-II expression both in vivo and in vitro. GH increased the relative expression from promoters P2 and P4, which may have implications on IGFII translation. In the human hepatoma cell line, HepG2, hypoxia had divergent effects on IGF-II mRNA expression and secretion. IGF-II mRNA expression increased, and is consistent with previous observations of stimulation of P3-promoter driven transcription. In contrast, there was a decrease in secretion of the IGF-II precursor form(s) of 14 kDa. This cell line will be useful for future studies of the regulation of transcription, translation, processing and secretion of IGF-II