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Snorri S. Thorgeirsson, M.D., Ph.D.

Laboratory of Experimental Carcinogenesis Head, Cellular and Molecular Biology Section Laboratory Chief Building 37, Room 4146A1 NCI-, NIH 37 Convent Drive MSC4262 Bethesda, MD 20892 Phone:   301-496-1935 Fax:   301-496-0734 E-Mail:   snorri_thorgeirsson@nih.gov Link: Other Homepage

Biography

Dr. Thorgeirsson joined the NCI in 1976 and has been the chief of the Laboratory of Experimental Carcinogenesis since 1981. He obtained his M.D. from the University of Iceland. He studied biochemistry and pharmacology with Sir Colin Dollery and Dr. Donald S. Davies at the Royal Postgraduate Medical School in London, England, and obtained his Ph.D. from the University of London. His research interests are centered on the application of transgenic mouse models as paradigms for human diseases and stem cell biology.

Research

Transgenic Mouse Models for Multistage Carcinogenesis and Hepatic Stem Cell Biology

NFkappaB and TGFbeta pathways. NFkappaB/Rel factors have been strongly implicated in the regulation of apoptosis, a key mechanism of normal and malignant cell growth control. In particular, a direct role of NFkappaB/Rel in the survival of hepatocytes has been demonstrated. We have used the normal and Ras- and Raf-transformed RLE cells to test the hypothesis that the transformed RLE cells have altered NFkappaB regulation leading to resistance of TGFbeta-1. The data demonstrate that NFkappaB is aberrantly activated in Ras- or Raf-transformed RLEs due to increased phosphorylation and degradation of IkBalpha protein. Furthermore, we demonstrated that inhibition of either IKK-1 or IKK-2 reduced focus-forming activity in Ras-transformed RLEs. Thus we conclude that these studies identified and elucidated a mechanism that contributes to the process of transformation of stem-like liver cells by oncogene Ras and Raf through the IkB kinase complex leading to constitutive activation of NFkappaB.

Helix-loop-helix proteins and hepatic stem cell differentiation. We have also explored the potential role of helix-loop-helix (HLH) proteins in the regulation of activation and differentiation of hepatic stem cells. The HLH family of transcription regulatory proteins are key regulators in numerous developmental processes. The class I HLH proteins, such as E12, are ubiquitously expressed. Class II HLH proteins, such as MyoD, Atonal, NeuroD/BETA 2 are expressed in a tissue-specific manner. We have identified E-box sequences in promoters/enhancers of a number of genes that both regulate and characterize liver-specific gene expression. These include HNF-1alpha, HNF-3alpha and 3gamma, HNF-4, and HNF-6, alpha-fetoprotein (AFP) as well as in the intergenic enhancer between albumin and AFP genes. We have therefore hypothesized that HLH proteins may exist that regulate both developmental pathways and cell lineage commitment in the liver. In an attempt to identify partners for the E12 protein that may exert control during liver development, we performed the yeast two-hybrid screen using the expression complementary DNA library from human fetal liver. A novel dominant inhibitory HLH factor, designated HHM (Human Homolog of Maid), was isolated and characterized. HHM is structurally related to the Id family and was highly expressed in brain, pituitary gland, lung, heart, placenta, fetal liver, and bone marrow. HHM physically interacted with E12 in mammalian cells in vitro. Although some similarities exist between the expression profiles of HHM and Id2, there are distinct differences best seen in fetal tissues. Recent results show that HHM can interact with E12, Cyclin D1, Grap2, and the HNF-4 promoter, suggesting that HHM may possess multifunctional capacity.

Regulation of NFkappaB in c-myc/TGFalpha tumors. We have shown that oncogenic Ras- or Raf-mediated transformation of rat liver epithelial (RLE) cells altered NFkappaB regulation through IKK complex activation, which rendered these cells more resistant to TGFbeta-1-induced apoptosis. Based on these findings, we hypothesized that disrupted regulation of NFkappaB could also be involved in tumor growth of liver cells in vivo. To test this hypothesis, we compared HCCs from the c-myc/TGFalpha mice to HCCs from c-myc single transgenic mice. The results show that NFkappaB is activated in HCCs from c-myc/TGFalpha mice, but not in tumors from the c-myc single transgenic mice, suggesting TGFalpha mediates induction of NFkappaB. Furthermore, activation of the IKK complex was observed in the HCCs from c-myc/TGFalpha mice, implicating this pathway in the NFkappaB induction.

Beta-catenin (Wingless/Wnt pathway). Mutations affecting phosphorylation sites in the beta-catenin gene have been implicated in the development of human and rodent hepatocellular carcinomas. To further investigate the involvement of this gene in hepatocarcinogenesis, we used several transgenic mouse models of hepatic tumors induced by overexpression of c-myc in the liver either alone or in combination with TGFalpha or TGFbeta-1. These studies suggest that nuclear translocation of beta-catenin and activation of Wingless/Wnt signaling may represent an early event in liver carcinogenesis, providing a growth advantage in a subset of hepatic tumors with a more differentiated phenotype. This is of considerable interest since mutations in beta-catenin are associated with a decreased loss of heterozygosity in human HCC. We have therefore hypothesized that development of liver cancer may advance via two broad pathways. The first pathway would involve beta-catenin activation, while the second one would generate genomic instability and produce a mutator phenotype.

Oxidative stress and DNA damage. Our previous work implicated oxidative DNA damage in the etiology of c-myc/TGFalpha but not c-myc associated hepatocarcinogenesis. It is of considerable interest that mice in which defective DNA repair was generated by targeting the excision repair cross-complementing gene (ERCC-1) have a strikingly similar liver phenotype to our c-myc/TGFalpha mice. We have therefore hypothesized that attenuation and/or disruption of DNA repair might be required for the accumulation of oxidative DNA lesions. To test this hypothesis, we have sought to determine whether inactivation of DNA repair pathways contributes to an increased chromosomal instability and acceleration of the neoplastic process in c-myc/TGFalpha mice. Taken together, our results imply that DNA repair responses are dramatically altered in young adult c-myc/TGFalpha mice.

Collaborators on this research include Marcello Arsura, University of Tennessee, Memphis; Hanne Cathrine Bisgaard, Roskilde University, Denmark; Carla Boccaccio, University Torino, Italy; Nicholas Dean, ISIS Pharmaceuticals, Carlsbad, CA; Joe W. Grisham, James Swenberg, and Ronald G. Thurman, University of North Carolina, Chapel Hill; Michael R. Jensen, European Institute of Oncology, Milan, Italy; Stefan Karlsson, Lund University, Sweden; Jeffrey Kopp, Glenn Merlino, Raji Padmanabhan, Nicholas C. Popescu, Elizabeth G. Snyderwine, and Unnur P. Thorgeirsson, NIH; Michael Muller, Wageningen University, The Netherlands; Peter Nagy, Semmelweis University, Budapest, Hungary; Richard Pestell, Albert Einstein Cancer Center, Bronx, NY; Carol Prives, Columbia University, New York; Alistair Strain, University Birmingham, UK; and Shuji Terai, Yamaguchi University School of Medicine, Yamaguchi, Japan.

This page was last updated on 6/12/2008.