胰臟腺癌(PDAC)是最棘手的癌症之一，其發生率近乎等於死亡率。儘管已經有相當多的研究報導，但至今仍無有效的治療方法來減少此疾病的致死率。大部份的胰臟腺癌是經由 K-Ras 致癌基因的活化和 Ink4a、p53-Arf 路徑被抑制等變異所產生，SMAD4 基因(TGF-β訊號主要調控者)去活化變異存在於大約 55% 的胰臟腺癌病例中。因此，為了在癌症生物學裡確定 SMAD4 基因對胰臟癌演進的影響機制，我們設計一系列實驗，用胰臟癌細胞株模組去剖析 SMAD4 缺失對 PDAC 細胞株的影響，和探討去活化 SMAD4 蛋白後與低氧壓/ TGF-β 的相互作用下對胰臟癌的轉移能力及抗藥性的調控作用。實驗結果顯示，將 SMAD4 重新送回 PDAC 細胞株中可對 HIF-1α、VEGF、FGF10、FGFR2 等影響癌細胞生存的基因有明顯的抑制其表達量，也可以看出 SMAD4 蛋白有抑制癌細胞轉移、抗藥性和血管新生的能力，我們推測是 SMAD4 抑制了那些生存基因的表達所造成的效果。這些詳細的調控機制目前還不明確，所以將來延續的研究目標，將朝著解開 SMAD4 訊息傳遞的路徑與各種下游相關蛋白之間的關連性為主。

Pancreatic ductal adenocarcinoma (PDAC) is one of the most insidious forms of cancer whose incidence nearly equals its death rate. Despite extensive research studies, no effective therapeutic approaches for diminishing the morbidity associated with this disease are available. PDAC is characterized by activating Kras mutations and inactivation of Ink4a and the p53-Arf pathway in virtually all cases, while SMAD4—a central regulator of Transforming growth factor-beta (TGF-β) signaling—is inactivated in 55% of PDAC. Our overall goal is to understand how perturbations in the inactivation of SMAD4 pathway contribute to the late stages of PDAC pathogenesis, and to elucidate the role of SMAD4 inactivation on the conversion of a benign form of the cancer to a more aggressive metastatic form. To address this important topic in cancer biology, we have devised a strategy to develop model cell lines to dissect the role of SMAD4 defect in PDAC cell lines and the potential synergistic effects of hypoxia and/or TGF-β1 upon SMAD4 inactivation in their metastatic properties. Experiment results showed SMAD4 restored in PDAC model cell lines were down regulate HIF-1α, VEGF, FGF10 and FGFR2 genes expression level, and also inhibited migration, chemoresistance and angiogenesis of cancer cells. We hypothesize that these effects are due to SMAD4 suppresses some cancer genes in PDAC. Further detailed investigations are also needed to fully elucidate the detail mechanisms for our findings here therefore, the future works of this study will go step on looking for those important downstream effect genes regulated by Smad4 protein in PDAC cells and try to find out the connection of all the dependence proteins.

Abstract in Chinese ------------------------------------------------- 1
Abstract in English -------------------------------------------------- 2
Abbreviations --------------------------------------------------------- 4
Introduction ------------------------------------------------------------ 6
Specific Aim --------------------------------------------------------- 15
Materials and Methods --------------------------------------------- 16
Results ---------------------------------------------------------------- 24
Discussion ------------------------------------------------------------ 29
Figures and Tables -------------------------------------------------- 35
References ------------------------------------------------------------ 51

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