The overall goal of the proposed studies is to directly access the role of IGF-II in hepatocarcinogenesis. IGF-II is primarily expressed in fetal tissues (1) and a gene knockout experiment has demonstrated that its expression is necessary for normal fetal growth (2). In the proposed studies, two transgenic mouse models, immortalized hepatocyte cell lines, and an IGF-II knockout mouse will be utilized. Transgenic mouse model utilizes the Major Urinary protein (MUP) promoter (3) to drive expression of a human IGF-II cDNA in the liver of adolescent and adult mice. The second transgenic mouse model utilizes SV40 Ag driven by the MUP promoter to induce malignant progression in the liver (4,5).
The Specific Aims of this proposal are: 1. To utilize recently developed IGF-II transgenic mouse lines study the effect of IGF-II expression in adolescent and adult mice and determine: (A) The time course of transgene expression, the hormone inducibility of transgene expression and characterize IGF-II induced liver pathology; (B) Whether the oncogenicity of chemical hepatocarcinogens and/or tumor promoters is enhanced or repressed by the presence of IGF-II in adult mouse liver; (C) Whether homozygous knockout of the IGF-II gene can protect the liver from hepatocarcinogenesis; (D) Whether naturally occurring maternal imprinting of the IGF-II gene serves a cancer suppressor or protective function. 2. To study the role of IGF-II in malignant progression of immortalized hepatocytes by determining whether: (A) IGF-II transforms or otherwise alters the growth properties of immortalized hepatocytes and (B) whether the ability of IGF-II to alter hepatocellular phenotype varies with the stage of hepatocytic carcinogenesis in SV40 T Ag transgenic mice (i.e. original hepatocytes, small cell foci, neoplastic nodules). 3. To study the effect of IGF-II expression on the growth requirements and properties of primary transgenic hepatocytes. We will determine whether IGF-II expression in transgenic hepatocytes substitutes for the Insulin or EGF requirements of primary cultured hepatocytes, and whether the growth properties or phenotype of the cells is altered in vitro. 4. If a causative role for IGF-II in hepatocarcinogenesis is established by the above experiments, then we will study the structure and function of IGF-II polypeptides which accumulate in HCC. Studies will include: (A) Characterization of the structure of the 15 Kd IGF-II polypeptide in HCCs; (B) Search for and characterization of IGF-II-receptor complexes and (C) Initial studies on the signal transduction capabilities of IGF-II-receptor complexes.
| Harris, T M; Rogler, L E; Rogler, C E (1998) Reactivation of the maternally imprinted IGF2 allele in TGFalpha induced hepatocellular carcinomas in mice. Oncogene 16:203-9 |
| Yang, D; Faris, R; Hixson, D et al. (1996) Insulin-like growth factor II blocks apoptosis of N-myc2-expressing woodchuck liver epithelial cells. J Virol 70:6260-8 |
| Rossetti, L; Barzilai, N; Chen, W et al. (1996) Hepatic overexpression of insulin-like growth factor-II in adulthood increases basal and insulin-stimulated glucose disposal in conscious mice. J Biol Chem 271:203-8 |
| Rogler, C E; Yang, D; Rossetti, L et al. (1994) Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice. J Biol Chem 269:13779-84 |
