癌症的生成可能藉由致癌基因的活化或是抑癌基因的突變缺失所導致。在許多癌症發生過程中經常伴隨有Pten基因缺失或突變之現象，顯示Pten基因在抑制癌症生成中扮演了重要的角色。由於大部分的腫瘤是來自上皮細胞的基因突變以及癌化所生成的，我們希望透過小鼠的誘導性組織專一性基因剔除系統來探討上皮細胞當中Pten的功能。我們成功的建立了單層上皮誘導性基因轉殖小鼠株並且進一步分析該小鼠的Cre重組酶活性，證實在許多內臟器官的單層上皮當中皆具有Cre重組酶的活性。同時我們也利用該基因轉殖小鼠來探討在腸道以及乳腺當中上皮細胞的譜系追蹤，證實具有Cre重組酶活性的細胞包含腸道幹細胞群，然而在乳腺當中並不包含幹細胞群。
進一步利用此基因轉殖小鼠將單層上皮中的Pten基因剔除後，發現約50%的小鼠會迅速發展出胰管腺癌和肝內膽道癌。除此之外，我們也檢視了Pten基因剔除公鼠當中攝護腺癌的進展。在為期十三週的研究期間內，大部分Pten基因剔除的攝護腺發展成高度惡性攝護腺增生瘤，僅有一隻小鼠被觀察到有攝護腺癌的產生。我們也發現到在攝護腺柱狀上皮中剔除Pten基因表現除了會造成柱狀上皮細胞的異常增生以外，也會造成基底細胞的增殖。透過細胞譜系追蹤的實驗，證實柱狀上皮細胞同時具有分化為柱狀上皮細胞和基底細胞的能力。而在男性荷爾蒙缺失的Pten基因剔除公鼠當中，我們觀察到荷爾蒙缺少並不能抑制攝護腺癌的發展，甚至會誘導出一群荷爾蒙非依賴性的基底細胞群增生。
總結研究結果，本實驗所建立的單層上皮誘導性Pten基因剔除小鼠可利用於探討在胰管腺癌、肝內膽道癌和攝護腺癌當中，Pten基因突變後所導致的致癌機轉，進一步可做為癌症的動物模式，提供臨床上試藥與治療的研究。

PTEN (phosphatase and tensin homolog deleted on chromosome ten) is an important tumor suppressor gene involving in the progression of several cancers. To investigate the role of PTEN in simple epithelial cell, we have generated a simple-epithelial specific Cre transgenic mouse and evaluated the Cre activity using reporter mice. We also demonstrate the application of this transgenic mouse in studying the epithelial lineage in intestine and mammary gland. Additionally, the simple epithelial-specific Pten-deficient mice develop PDAC and cholangiocarcinoma, which are proceeded in a rapid progression than previous studies. We show that the prostate cancer progression is restricted in the HGPIN stage in these mice during a study period of 13 weeks. Surprisingly, the hyperplasia of both the luminal and the basal compartment are observed and these cells are derived from the Pten-deficient luminal lineage. Finally, we performed the androgen deprivation therapy in the Pten-deficient prostate. However, androgen ablation cannot attenuate the tumor progression and even give rise a androgen-independent basal population.
Taken together, our preliminary results implicated that simple epithelial-specific Pten-deficient mouse can be utilized to gain insight into the role of PTEN in the maintenance of normal epithelial homeostasis and in the pathogenesis of PDAC, cholangiocarcinoma and prostate cancer. Furthermore, this Pten-deficient mouse might provide a mouse model to study the target therapy of these cancers.

Chinese Abstract ……….1
English Abstract ……….2
I. Introduction ……….3
I-1. General introduction of PTEN ……….3
I-2. Physiological role of PTEN in human and mouse ……….4
I-2-1. Germline and somatic mutations of PTEN in human ……….4
I-2-2. Physiological functions of PTEN in mouse tissue ……….5
I-3. The role of PTEN in prostatic tumorigenesis ……….6
I-3-1. Prostate physiology in human and mouse ……….6
I-3-2. Pathogenesis and the role of PTEN in prostate cancer ……….7
I-4. Characteristics of Keratin 8 and Keratin 18 in simple epithelium ……….9
I-4-1. Keratins in epithelial tissues ……….9
I-4-2. Genetic characteristics of K8 and K18 ……...10
I-4-3. Keratin 8 and Keratin 18 in simple epithelium ……...10
I-4-4. K8 and K18 in carcinomas ……...11
II. Materials and Methods ……...13
II-1. Mice ……...13
II-2. Genotyping ……...15
II-3. Pharmacological administration ……...17
II-4. Tissue processing, embedding and section ……...17
II-5. Whole mount X-gal staining ……...18
II-6. Section X-gal staining ……...19
II-7. Hematoxylin and Eosin staining (HE staining) ……...20
II-8. Immunohistochemistry staining (IHC staining) ……...20
II-9. Immunofluorescent staining (IF staining) ……...21
II-10. Indirect immunofluorescence with tyramide signal amplification ……...22
II-11. TUNEL staining ……...23
II-12. Oil-Red O staining ……...24
II-13. Castration and androgen administration ……...24
II-14. Statistical analysis ……...25
III. Results ……...26
III-1. Generation of the K18-EGFP, K8-CreERT transgenic mice ……...26
III-2. Application of the K18-EGFP, K8-CreERT transgenic mice in cell lineage tracing of intestines and mammary glands ……...27
III-3. Establishment of simple epithelia specific Pten knockout mice ……...28
III-4. Loss of Pten causes pancreatic ductal adenocarcinoma in the K18-EGFP, K8-CreERT; Ptenfx/fx mice ……...29
III-5. Loss of Pten causes cholangiocarcinoma in the K18-EGFP, K8-CreERT; Ptenfx/fx mice ……...30
III-6. Activation of Notch signaling in the K18-EGFP, K8-CreERT; Ptenfx/fx mice ……...31
III-7. Loss of Pten causes steatosis in liver in the K18-EGFP, K8-CreERT; Ptenfx/fx mice ……...32
III-8. Prostate tumor progression in the K18-EGFP, K8-CreERT; Ptenfx/fx mice ……...32
III-9. Loss of Pten activates AKT phosphorylation in the Pten-deficient prostate ……...33
III-10. Increased proliferative cells during prostatic cancer progression ……...34
III-11. Characterization of the epithelium compartment in the prostate of Pten-deficient mice ……...35
III-12. Capability of bipotentiality in prostatic luminal cells ……...37
III-13. The hyperplastic luminal cells and basal cells are both derived from luminal cells in Pten-deficient mice ……...38
III-14. Androgen ablation does not retard the prostate cancer progression ……...38
IV. Discussions ……...40
IV-1. Establishment of the K18-EGFP, K8-CreERT transgenic mice ……...40
IV-2. The tumor suppressive functions of Pten in the pancreas and the bile duct ……...41
IV-3. The tumor suppressive functions of Pten in the prostate ……...45
IV-3-1. Loss of Pten in prostatic luminal compartment shows longer tumor latency ……...45
IV-3-2. Capability of bipotentiality in luminal cells of the Pten-deficient prostate ……...45
IV-3-3. Androgen ablation cannot suppress the Pten-deficient prostate cancer progression ……...47
IV-3-4. Hypothesis for the physiological function of Pten in luminal cells ……...48
V. References ……...50
VI. Figures ……...60
VII. Tables ……...99

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