癌症是重要的人類健康問題，胃癌及食道鱗狀細胞癌是常見且致命的疾病。雖然整合運用了各種的治療方式，多數病人依然死於疾病或治療引起的副作用，為了改善現有的及發展新穎的診斷與治療癌症的方式，癌症致病機轉必須更清楚地被研究。
RUNX3是癌症抑制基因，它的抑癌作用最早是在胃癌中被確認，在大約八成的胃癌中RUNX3會有低表現或失去功用的情形。雖然RUNX3已知會透過調控許多分子的表現或作用而抑制胃癌的生成，但是其機轉仍未被透徹地瞭解。所以我的博士論文研究胃癌中RUNX3對β-catenin/ cyclin D1的調控，RUNX3被發現會抑制Akt1的轉錄並降低Akt1的表現量，進而促使β-catenin被分解及cyclin D1的低表現，結果顯示在胃癌中RUNX3的失去功能會促使癌化的進行，其機轉包括Akt1/ β-catenin/ cyclin D1訊息途徑的活化。
β-catenin與cyclin D1也都是Pin1基質，而Pin1已被證實會藉由調控許多抑癌或致癌分子而促使癌症的生成。所以我的博士論文研究食道鱗狀細胞癌中RUNX3對β-catenin與cyclin D1的調控，以細胞株的實驗證明了將Pin1的表現量降低會抑制 β-catenin與cyclin D1的表現量及食道鱗狀細胞癌的生成，也確認在接受手術治療的食道鱗狀細胞癌病患中，Pin1的高表現量與不良預後有相關性，上述結果顯示Pin1會透過β-catenin與cyclin D1而增進食道鱗狀細胞癌惡性度。
綜言之，β-catenin與cyclin D1在胃癌中會被RUNX3抑制，而在食道鱗狀細胞癌中會被Pin1正相關地調控，我的博士論文讓上消化道癌症的致病機轉更清楚地被了解，期望對未來癌症診療業務的改進與發展有所助益。

Cancer is one of major health issues. Gastric cancer and esophageal squamous cell carcinoma (ESCC) are common and fatal malignancy. Despite multi-modality therapies, most patients eventually die from the disease or treatment-related complications. More comprehensive investigations of carcinogenesis and tumor progression are necessary for developing novel diagnostic and therapeutic strategies for these cancers.
RUNX3 is recognized as a tumor suppressor. The tumor suppressive functions of RUNX3 were first reported in gastric epithelial cells. RUNX3 was inactivated by gene silencing or protein mislocalization in more than 80% of gastric cancers. Although restoration of RUNX3 in gastric cancer cells could inhibit tumorigenesis through regulating several target genes, the mechanisms were not clearly understood. The role of RUNX3 in regulating β-catenin and cyclin D1 in gastric cancer was studied in my thesis. RUNX3 repressed Akt1 expression through transcriptional inhibition. Two RUNX3-binding sites on Akt1 promoter were identified. The inhibition of Akt1 facilitated β-catenin degradation followed by cyclin D1 downregulation. The data suggested loss of RUNX3 in gastric cancer promoted tumorigenesis through Akt1/β-catenin/cyclin D1 signaling pathway.
β-catenin and cyclin D1 are well known substrates of Pin1 which is a peptidyl-prolyl isomerase and promotes oncogenesis by regulating multiple oncogenic signaling at various levels. Pin1/β-catenin/cyclin D1 signaling pathway in ESCC was investigated. The experimental evidences were provided that Pin1 knockdown inhibited expression of β-catenin/cyclin D1 and tumorigenesis of ESCC cells. The inhibited tumorigenesis in cells with Pin1 knockdown was partially recovered by cyclin D1 restoration. In addition, high Pin1 expression was correlated with poor prognosis of ESCC patients. The results supported that Pin1 may promote ESCC aggressiveness through β-catenin and cyclin D.
In summary, β-catenin and cyclin D1 are repressed by tumor suppressor RUNX3 but positively regulated by Pin1 in cancers of upper digestive tract. The results of my thesis can help people understand carcinogenic mechanisms and provide rationales for developing novel target therapy of cancer in the future.

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