| Summary: | 碩士 === 國立中山大學 === 生物醫學科學研究所 === 94 === It has been demonstrated that overexpression of Pin1, a novel cell cycle regulator, in human breast cancer and might play an important role in tumorigenesis. However, the role of Pin1 and whether Pin1 is overexpressed in esophageal squamous cell carcinoma (ESCC) remained unclear. There are two specific aims in this study. The first specific aim is to study the correlation between Pin1 and human ESCC cancer. The second specific aim is to discover drugs that can intervent the Pin1 mediated signaling and provide a novel chemotherapy for human ESCC. In this dissertation, we have demonstrated that Pin1 was overexpressed in more than 65% of clinical esophageal cancer tissues and its level correlated with β-catenin and Cyclin D1 expression by western blotting and immunohistochemistry analyses. The RT-PCR results suggested that Pin1 overexpression maybe due to the up-regulation of Pin1 transcription. By statistic analysis, we have demonstrated that ESCC patients with Pin1 overexpression had significantly poorer survival rate than those non-Pin1 overexpression patients (p< 0.001). Pin1 therefore can be used as a prognosis marker for ESCC. In addition, we have demonstrated that Pin1 suppression by shRNA could downregulate β-catenin and Cyclin D1 expression and inhibit ESCC cell proliferation efficiently. Taken together, these results suggest that Pin1-β-catenin and Cyclin D1 could be used as a potential chemotherapy target for ESCC. In order to discover novel drugs in the chemoprevention or therapy of human ESCC, we screened a chemical library using cell proliferation assay. Among them, compound VGHKS-040 not only effectively inhibited the cell proliferation rate in ESCC cell lines with IC50 value of 4.8±0.6μM but also abated protein levels of Pin1, β-catenin, and cyclin D1. By colony forming assay as well as the Xenograft SCID and nude mice model, we have demonstrated that VGHKS-040 can inhibit the tumor growth in vitro and in vivo. These results suggested that VGHKS-040 provide a new avenue for chemotherapy of esophageal squamous cell carcinoma.
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