臺灣博碩士論文加值系統

PI3K/Akt訊息傳導路徑是細胞生長、細胞存活、細胞運動、血管生成及細胞新陳代謝的必須路徑。Phosphatase and tensin homolog (PTEN)為抑癌基因，其為PI3K/AKT路徑中有效的抑制者，藉由將PIP3去磷酸化，進而防止Akt過度活化，若PTEN發生突變將使Akt過度活化，而導致癌症的發生。PTEN基因拷貝數缺失的現象在膀胱癌及上泌尿道上皮癌研究中觀察到；此外，膀胱癌及早期非小細胞肺癌研究更進一步報導過PTEN蛋白低表達而促使pAkt蛋白活躍的現象。因此本研究目的在於探討PI3K/Akt路徑中PTEN在上泌尿道上皮癌的角色，其與Akt蛋白相互關係及臨床價值。本篇研究使用免疫化學組織染色法偵測PTEN、pAktS473及pAktT308在六十五個上泌尿道上皮癌樣本的蛋白表達量，並結合臨床資料進行統計分析。研究結果顯示，PTEN、pAktS473及pAktT308在正常組織中蛋白表達量皆大於腫瘤組織。此外，高腫瘤分期的病人PTEN蛋白細胞質低表達較多於低腫瘤分期病人；高惡性度病人pAktT308蛋白細胞核及細胞質低表達遠較於低惡性度病人多。然而，PTEN基因突變研究比較於PTEN、pAktS473及pAktT308蛋白統計結果卻不具顯著差異性。在單變量與多變量分析中PTEN蛋白細胞質低表達者比高表達者危險率高 (3.14，3.29倍；P值為0.016，0.017)；pAktS473蛋白細胞質高表達者比低表達者危險率高 (2.71，2.64倍；P值為0.019，0.027)；有轉移比沒有轉移的危險率高 (3.55，2.73倍；P值為0.003，0.031)；高腫瘤分期比低腫瘤分期的危險率僅於單變相分析中有意義 (3.4倍，P值為0.001)。其次，KM存活率分析中則顯示，高腫瘤分期、有轉移者、細胞質PTEN低表達且pAktS473高表達其高死亡率有顯著意義 (P值分別為0.006，0.001與<0.001)。因此，根據統計結果顯示PTEN、pAktS473及pAktT308蛋白或許可以做為上泌尿道上皮癌病人良好的預後指標。

The PI3K/Akt pathway is considerated to be essential for various cellular processes including cell growth, survival, cell motility, angiogenesis and cell metabolism. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene and presents a negative regulator of the PI3K/Akt pathway by dephosphorylation of PIP3 to prevent Akt hyperactivation. Loss of PTEN expression and hyperactivation of Akt can result in tumorigenesis. Previous studies indicated that PTEN gene deletions were observed in early bladder cancer and upper tract urothelial carcinoma (UTUC). Other studies showed PTEN protein absence and pAkt protein expression in bladder cancer and non-small-cell lung carcinoma. We aim to evaluate the expression status and prognostic value of PTEN and PI3K/Akt pathway in UTUC. Archival formalin-fixed paraffin-embedded (FFPE) tissues from 65 UTUCs were performed by immunohistochemistry for PTEN, pAktS473 and pAktT308. Expression of each protein were compared with clinicopathologic parameters. PTEN, pAktS473 and pAktT308 protein expression were higher in adjacent normal tissues than tumor tissues. Cytoplasmic PTEN protein low expression was higher in high stage compared with low stage; nuclear and cytoplasmic pAktT308 protein low expression were higher in high grade compared to low grade. PTEN gene alternation was not associated with PTEN, pAktS473 and pAktT308 protein. In univariate analysis and multivariable analysis, cytoplasmic PTEN protein low expression (HR = 3.14, 3.29; P = 0.016, 0.017), cytoplasmic pAktS473 protein high expression (HR = 2.71, 2.64; P = 0.019, 0.027), metastatic (HR = 3.55, 2.73; P = 0.003, 0.031) had poor prognosis, however, lower pT stage was only significant in multivariable analysis (HR = 3.48, P = 0.01). Kaplan-Meier survival analysis showed that high tumor grade, metastatic, cytoplasmic PTEN (-)/ pAktS473(+) had poor survival (P - value were 0.006, 0.001 and <0.001, respectively). In conclusion, our findings implicate that PTEN, pAktS473 and pAktT308 protein appear to be an important indenpendent prognostic factor in UTUC patients.

中文摘要 i
Abstract ii
誌謝 iii
目錄 iv
表目錄 vii
圖目錄 viii
第一章 研究背景 1
1.1 研究背景 1
1.1.2 上泌尿道上皮癌簡介 1
1.2 PTEN在PI3K/Akt路徑與癌症之間的關係 3
第二章 研究動機與目標 5
2.1 研究動機 5
2.2 研究目標 6
第三章 材料與方法 7
3.1 材料 7
3.1.1 材料來源 7
3.1.2基本資料與病史 7
3.2 組織染色 9
3.2.1 H&E stain 9
3.3.2 免疫組織化學染色法 10
3.4 評估免疫組織化學染色 12
3.5 統計分析方法 12
第四章 實驗結果 13
4.1 病例臨床數據 13
4.2 免疫化學染色結果 13
4.2.1 蛋白在腫瘤及鄰近正常組織之免疫化學染色結果 13
4.2.2 PTEN在細胞核與細胞質之蛋白表達量比較 23
4.2.3 pAktS473在細胞核與細胞質之蛋白表達量比較 23
4.2.4 pAktT308在細胞核與細胞質之蛋白量比較 24
第五章 結果討論 26
5.1探討蛋白免疫化學染色結果 26
5.1.1 探討PTEN蛋白表達量 26
5.1.2 探討pAktS473蛋白表達量 26
5.1.3 探討pAktT308蛋白表達量 27
5.2 探討上泌尿道上皮癌蛋白表達之臨床意義 28
5.2.1 探討PTEN蛋白表達之臨床意義 28
5.2.2 探討pAkt S473蛋白表達之臨床意義 32
5.2.3 探討pAktT308蛋白表達之臨床意義 34
5.3 探討PTEN基因特異性與蛋白表達之相關性 36
5.3.1 探討PTEN基因特異性與PTEN蛋白表達之相關性 36
5.3.2 探討PTEN拷貝數缺失與pAktS473蛋白表達之相關性 38
5.3.3 探討PTEN拷貝數缺失與pAktT308蛋白表達之相關性 39
5.4 探討臨床資料與蛋白表達之單變量分析 40
5.4.1 探討上泌尿道上皮癌臨床資料之單變量分析 40
5.4.2 探討上泌尿道上皮癌蛋白表達之單變量分析 42
5.5 探討臨床資料與蛋白表達之多變量分析 44
5.6 探討上泌尿道上皮癌臨床資料之總存活率 46
5.6.1探討上泌尿道上皮癌臨床資料之總存活率 46
5.6.1探討上泌尿道上皮癌腫瘤分期之總存活率 48
5.6.2 探討上泌尿道上皮癌轉移症狀之總存活率 50
5.7 探討上泌尿道上皮癌蛋白表達之總存活率 51
5.7.1 探討上泌尿道上皮癌PTEN蛋白表達之總存活率 51
5.7.2 探討上泌尿道上皮癌pAktS473蛋白表達之總存活率 55
5.7.3 探討上泌尿道上皮癌pAktT308蛋白表達之總存活率 58
5.7.4 探討蛋白共表達之總存活率 60
第六章 結論 68
參考文獻 70
附錄 77
A 長庚醫療財團法人人體試驗倫理委員會臨床試驗同意證明書 77
B 2017美國癌症研究協會 (AACR) 年度會議論文發表 79

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