Our research focuses on to define the molecular mechanisms of hepatocarcinogenesis. Currently we are investigating how the Wnt signaling pathway is involved in the development and/or progression of hepatocellular carcinoma (HCC). HCC is one of most common and devastating malignant disease worldwide. Neverthless, the molecular pathogenesis of HCC are largely unknown. Therefore, our effort to understand the effect of this pathway on development of HCC should yield new avenues for HCC treatment.
Hepatocellular carcinoma (HCC) is the major primary malignant tumor of the liver. Although viral etiological factors have been identified, the molecular mechanisms that contribute to tumor progression during hepatocarcinogenesis remain largely unknown. There is increasing evidence that alteration of the Wnt/Frizzled signaling pathway is a common early event in the molecular pathogenesis of HCC and is associated with tumor development and/or progression. Recently, we have made several observations: 1) a specific human Frizzled 7 (FZD7) receptor was overexpressed in human HCC cell lines, tumor samples, and HCC tumors derived from transgenic models. The expression levels of FZD7 were functionally correlated with increased cell motility and invasion. In addition, accumulation and nuclear translocation of ß-catenin was observed in HCC cell lines and tumor samples as the result of FZD7 overexpression. 2) Up-regulation of FDZ7 was also associated with downstream activation of this pathway in both dysplastic tissue and tumors. 3) More importantly, we have recently identified human Wnt-3 and Wnt-11 as the probable natural ligands for FDZ7 receptors. These findings suggest that up-regulation of the Wnt signaling pathway contributes to the development of HCC. Moreover, identification of Wnt-3 and Wnt-11 provides an opportunity to study general molecular mechanisms involved in murine and human hepatocarcinogenesis. Based on our findings we are currently focusing on 1) the role of Wnt pathway activation during hepatocarcinogenesis, 2) Wnt ligand expression and subsequent activation of downstream components of the ß-catenin pathway in human tumors, adjacent dysplastic tissue, and uninvolved liver, 3) determining if blocking Wnt ligand action has anti-tumor effects in animal models of hepatocarcinogenesis, 4) the expression profile of FZD receptors and the mechanisms of the canonical Wnt pathway activation in HCC, 5) TCF transcriptional factor isotypes and their target gene(s) in HCC. Since the identification of secreted Wnt ligands and how they signal through FZD7 receptors to downstream components is unknown, the relative contributions of canonical versus non-canonical pathways to HCC tumor formation may now be explored in some detail. These investigations may provide novel molecular targets for this devastating disease.
R21AA0205878 (PI: Kim, Miran) 2012-2014
Role of Wnt signaling in chronic alcoholic liver disease
P20RR015578-06 (PI: Sedivy, John) 2005-2010
National Institutes of Health / National Center for Research Resources (NIH/NCRR) Center for Cancer Signaling Networks - "Wnt Signaling in Hepatocellular Carcinoma"
Role: a project leader (Total cost for this project: $875,530)
R37CA35711 (PI: Wands JR) 2000-2010
NIH/National Cancer Institute (NCI)
Pathogenesis, Immunodiagnosis, and Therapy of HCC.