This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.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. Increasing evidence indicates that aberrant activation of the Wnt/Frizzled/ -catenin signaling pathway is associated with tumor development and/or progression, and is the most common genetic abnormality identified thus far. 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 -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.
Our specific aims are as follows:
Specific Aim 1 - Explore the role of Wnt pathway activation during hepatocarcinogenesis.
Specific Aim 2 - Examine Wnt ligand expression and subsequent activation of downstream components of the -catenin pathway in human tumors, adjacent dysplastic tissue, and uninvolved liver.
Specific Aim 3 - Determine if blocking Wnt ligand action has anti-tumor effects in animal models of hepatocarcinogenesis. 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.
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