Liver-Related Work

1. Discovery of Hepatocyte Growth Factor (HGF) and its receptor MET. Earlier studies had documented that after partial hepatectomy, there are circulating hepatocyte mitogens in the peripheral blood. Using hepatocyte cultures as bioassays, our lab (and two other independent laboratories in Japan) discovered and identified Hepatocyte Growth Factor as the circulating mitogen. Subsequently, in collaboration with Dr. Comoglio in Torino, Italy, we identified the product of the c-met oncogene as the HGF receptor. In addition to their importance in liver regeneration (to which the rest of my studies of these two proteins was dedicated), HGF and MET have developed a huge literature of findings related to their role in development, function and neoplasia of most tissues. In PubMed, there are currently 7813 publications listed on HGF and 4679 on MET.
2. Early signaling pathways triggering liver regeneration. The first cells of the liver to enter into proliferation during liver regeneration are hepatocytes. We identified EGFR and MET as the only two mitogenic receptor tyrosine kinases associated with hepatocyte proliferative signals and demonstrated their early activation in the regenerative process and the dependence of the regenerative events on their function. 
3. Mechanisms of termination of liver regeneration. When regeneration ends, liver returns to the exact liver-to body weight ratio as prior to regeneration. We named this function “hepatostat,” a term now widely applied. We demonstrated that termination of liver regeneration is a very complex process, controlled by signaling of integrins via integrin linked kinase (ILK) and pericellular proteins such as Glypican 3 (GPC3). Interference with these pathways affects the final outcome of regeneration and the final liver weight.
4. Transdifferentiation of hepatocytes to biliary cells and vice-versa as the alternative epithelial pathways when either epithelial hepatic component is prevented from regenerative repair.
5. Genomic alterations and associated signaling pathways in human hepatocellular carcinoma. This is the most recent research direction of our laboratory. We did very high detail analysis of gene copy number variation (CNV) in 98 cases of human hepatocellular carcinomas (HCC), aiming to identify 800-2000 base pair deletions or amplifications associated with HCC. We then ranked the genes identified based on the number of cases associated with CNV for each gene. The gene with the highest frequency of HCC-associated CNV was Leucocyte Specific Protein 1 (LSP1), with 52/98 cases having either deletions or amplifications of the C-terminal region of the gene (acting as dominant negative signals). We have now carried research for a year and identified LSP1 as a binding protein for the protein KSR, the latter acting as a scaffold controlling the RAFMEK-ERK signaling, a very important mitogenic signal for hepatocytes.

Professor and Chair
Department of Pathology