在台灣肝癌是常見的癌症之一，肝癌目前的治療方式，主要有手術切除、放射線療法、化學治療與標靶治療等。無論如何，整體的肝癌預後是很差的。此篇研究主要在探討非固醇類抗發炎藥物希樂葆在肝癌治療的效果與機轉。希樂葆是一個第二型環氧化酶(COX2)抑制劑，有許多文獻指出希樂葆具有預防癌症的效果，尤其是大腸癌的預防。但是希樂葆在肝癌的治療效果與抗癌機轉卻不清楚。我們研究發現希樂葆在大鼠原位肝癌的模式中具有預防與治療的效果，而主要的機轉是經由腫瘤抑制基因PTEN的上調去調控Akt路徑與腫瘤微環境中的前列腺素E2(PGE2)的抑制而減少癌症幹細胞的數量與功能。我們也發現PGE2促進癌症幹細胞的生長主要是經由EP4受體的活化。
蕾莎瓦是目前唯一治療肝癌的標靶藥物，不只價格昂貴而且治療效果有限。希樂葆可以明顯的抑制蕾莎瓦誘導的Akt活化，在細胞實驗發現希樂葆可以加強蕾莎瓦抑制細胞增生、聚落形成與細胞移動的效果。在動物實驗顯示希樂葆增強了蕾莎瓦抑制肝腫瘤生長的能力。肝癌細胞株長期與蕾莎瓦培養(一~八個月)會篩選出具有抗藥性的細胞株。幹細胞相關基因會隨著培養的時間上升，另外也伴隨著Akt磷酸化的增加。希樂葆可以抑制蕾莎瓦抗藥性增加的幹細胞球、邊緣細胞群與不對稱分裂。從實驗的數據顯示，當肝癌患者出現蕾莎瓦的抗藥性時，希樂葆治療或許可以當作治療肝癌的另一種選擇。

Hepatocellular carcinoma (HCC) is the one of most common malignancies in Taiwan. Current HCC therapies include surgery, chemotherapy, radiofrequency ablation and target therapy. However, the overall prognosis for HCC remains poor. The aim of study is to evaluate the therapeutic efficacy and mechanism of non-steroidal anti-inflammatory drug (NSAID) celecoxib in HCC. Celecoxib is a cyclooxygenase 2 (COX-2) inhibitor. Many reports indicate celecoxib shown chemopreventive effect in many malignancies, especially in colon cancer. But the effect and anti-cancer mechanism of celecoxib in liver cancer is unclear. The present study has further demonstrated the therapeutic efficacy of celecoxib in rat orthotopic HCC model. The mechanism is celecoxib inhibited cancer stem cells expansion and function through up-regulating tumor suppressor gene PTEN to regulate Akt pathway and reducing tumor microenvironmental prostaglandin E2 (PGE2). Moreover, PGE2 induced the expansion of hCSCs mediated EP4 receptor activation.
Sorafenib is the only target therapeutic drug for HCC treatment. However, the cost of Sorafenib therapy for HCC is high with limited efficacy in prolonging survival. Celecoxib can inhibit the sorafenib-induced Akt activation. Celecoxib enhanced the sorafenib-induced suppression of cell proliferation, colony formation and cell migration in vitro. Celecoxib enhanced the sorafenib-induced tumor growth suppression in vivo. Long-term culture with sorafenib (1~8 months) can select sorafenib-resistant hepatoma cells. Stemness genes can be up-regulated time-dependently. Moreover, the phosphorylation of Akt was also increased. Celecoxib inhibited sorafenib resistance-promoted sphere formation, side-population and asymmetric cell division. From our study, celecoxib is a choice for HCC therapy after patient show sorafenib-resistance.

The authorization of oral members for research dissertation ⅰ
Acknowledgement ⅱ
Abstract in Chinese ⅲ
Abstract in English ⅳ-ⅴ
Chapter 1. The therapeutic efficacy and mechanism of celecoxib in rat orthotopic hepatocellular carcinoma
1-1 Introduction 1-4
1-2 Meteials and methods 5-16
1-3 Results 17-26
1-4 Discussion 27-33
1-5 Figures and legends 34-58
Chapter 2. The potential of celecoxib as an adjuvant therapy with sorafenib for liver cancer
2-1 Introduction 59-62
2-2 Meteials and methods 63-69
2-3 Results 70-75
2-4 Discussion 76-78
2-5 Figures and legends 79-96
Conclusion 97-98
Future works 99
References 100-114
Publication and Conferences 115

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