博士 國防醫學院 醫學科學研究所 98 Head and neck cancer is the sixth most common type of cancer. Most head and neck cancers are squamous cell carcinomas (SCCHN) that develop in the upper aerodigestive epithelium after exposure to carcinogens such as tobacco and alcohol. Recent studies have revealed that a plethora of genetic events leading to the inactivation of tumor-suppressor genes or activation of proto-oncogenes, or both, govern the development of SCCHN. Epidermal growth factor receptor (EGFR) protein is overexpressed in more than 90% of SCCHN relative to normal tissue, and high expression is associated with poor disease control. Surgery and radiotherapy have long been the major treatment approaches. Recently, a new class of agents, the EGFR inhibitors, has shown clinical benefit in this disease. Presently, no established biomarker and no chemopreventive agent are of proven benefit in SCCHN. Beta-catenin is involved in two apparently independent processes, cell-cell adhesion and Wnt signal transduction. The Wnt/Beta-catenin pathway plays important roles in tumor formation. In the absence of Wnt, cytoplasmic Beta-catenin protein is constantly degraded by the action of the Axin complex, which is composed of the scaffolding protein Axin, the tumor suppressor APC, CK1, and GSK-3β. Therefore, Beta-catenin should not translocate to the nucleus and thus its target genes are not activated. The Wnt/Beta-catenin pathway is activated when a Wnt ligand binds to Frizzled (Fz or Fzd) receptor and thereby to the stabilization of Beta-catenin, which accumulates and travels to the nucleus to form complexes with T cell factor/lymphoid enhancer factor (TCF/LEF) and activates Wnt target genes, such as c-myc and cyclin D1 expression. Tumor genetics revealed that mutations in members of the Wnt/Beta-catenin pathway, such as APC and Beta-catenin, and mutations that activate the Wnt/Beta-catenin pathway promote stabilization of Beta-catenin and induce its nuclear accumulation. However, for some cancers, Beta-catenin accumulates in the nucleus even though mutation of Beta-catenin or APC is rare. Therefore, it is possible that mechanisms other than mutation are involved in the aberrant Beta-catenin expression observed in tumors. Previously, we and others reported that aberrant expression of Beta-catenin was common in SCCHN and this change correlated with the malignancy index and patient prognosis. In the literature to date, no evidence of APC and Beta-catenin mutation has been available for SCCHN. Thus, in SCCHN, molecular events other than mutations in Beta-catenin and APC may be responsible for the activation of the Wnt/Beta-catenin signaling pathway and the cytoplasmic/nuclear expression of Beta-catenin. However, the molecular mechanisms that lead to aberrant expression of Beta-catenin in SCCHN are unclear and the mechanisms by which Beta-catenin promotes activation of target genes are also not well understood. We used two types of SCCHN cell models to dissect critical events that regulate Beta-catenin stability and location, from Wnt antagonists (SFRPs) to the EGFR signaling, and nuclear machinery that mediates Beta-catenin-dependent transcription. In addition, we studied the clinicopathological and prognostic significance of Wnt antagonists (SFRPs), EGFR, Beta-catenin, and target genes regulation. Part one – In the cell model of mucoepidermoid carcinoma in salivary gland, we investigated the possible involvement of Wnt antagonist (SFRP1) methylation and expression in the aberrant distribution of Beta-catenin. Part two – In the cell model of oral cancer, we examined the effect of EGFR signaling on the nuclear accumulation of Beta-catenin and the mechanisms by which Beta-catenin promotes activation of target genes.