- 學位論文
脯氨酸導引蛋白質激酶FA在各種癌病的存活及預後的共通關鍵性角色
Prognostic role of proline-directed protein kinase FA (PDPK FA) in cancer progression and patient survival: a common molecular signature in different types of cancers
摘要
目的：分子、細胞及動物的實驗已證實過度表現的脯氨酸導引蛋白質激酶FA (PDPK FA) 被認為對於人類癌細胞的腫瘤形成、侵犯、轉移等是必備因子。然而，PDPK FA 在癌症病人的預後角色上所知甚少。本論文將完整地探討癌症病人開刀後，PDPK FA和其預後的相關性。 病人和方法：利用免疫組織染色法分析275位癌症病人 (包含167位頭頸部麟狀細胞癌病人、74位大腸直腸癌病人、以及34位食道癌病人) 外科切除的腫瘤切片中，PDPK FA的表現情形。腫瘤細胞核具PDPK FA高度濃染者是PDPK FA陽性表現的主要評估依據。所得資料進一步利用醫學統計進行存活分析。 結果：在167位頭頸部麟狀細胞癌的病人中，PDPK FA陽性表現的比率為41.3% (69/167)，在統計上，這些PDPK FA陽性表現的病人有意義的呈現較差的預後狀況，如較易復發、轉移和死亡(P<0.001)。克氏多變項比例風險模式進一步建立PDPK FA在頭頸部麟狀細胞癌的疾病惡化和病人存活上都是最強的獨立預後預測指標(復發風險比為3.063、死亡風險比為4.192，P<0.001)。PDPK FA若同時合併臨床上已建立的預後參數做存活分析，PDPK FA過度表現仍能相當明確地預測頭頸部麟狀細胞癌症病人將有一個不好的預後狀況。最後，線性回歸模式分析顯示已建立的PDPK FA 在預測頭頸部麟狀細胞癌症病人開刀後接受輔助性治療的反應是一個非常強的預測分子，PDPK FA陰性表現的病人接受輔助性治療的勝算比為12.581，統計上達到P<0.001的顯著意義。進一步，若合併74位大腸直腸癌以及34位食道癌的病人，也有相同的臨床意義產生，在這些癌症病人中，PDPK FA陽性表現的比率為41.8% (115/275)，在統計上，這些PDPK FA陽性表現的病人有意義的呈現較差的預後狀況，如較易復發、轉移和死亡(P<0.001)。克氏多變項比例風險模式進一步建立PDPK FA在癌症的疾病惡化和病人存活上都是最強的獨立預後預測指標(復發風險比為3.980、死亡風險比為5.815，P<0.001)。PDPK FA若同時合併臨床上已建立的預後參數做存活分析，PDPK FA過度表現仍能相當明確預測病人將有一個不好的預後狀況。最後，線性回歸模式分析顯示已建立的PDPK FA 在預測癌症病人開刀後接受輔助性治療的反應是一個非常強的預測分子，PDPK FA陰性表現的病人接受輔助性治療的勝算比為11.911，統計上達到P<0.001的顯著意義。 結論：本論文建立PDPK FA在癌症經外科切除後預後的重要性，無論是單獨以頭頸部麟狀細胞癌或是合併上食道癌、大腸直腸癌的角度切入，這些結果都和過去研究發現PDPK FA在促進癌症快速惡化的致命性角色一致，PDPK FA是個新的訊號傳遞分子可用以預測癌症惡化和病人存活。綜言之，PDPK FA在癌症病人開完刀後預後的預測與治療上是個全新、可矯正的、並且似乎是一個共通的訊號傳遞標的分子。
關鍵字
脯氨酸引導蛋白質激酶FA並列摘要
Purpose: The molecular, cellular and animal studies have established that overexpressed proline-directed protein kinase FA (PDPK FA) is essential for the development of tumorigenesis, invasion, and metastasis of human cancer cells. However, the prognostic role of PDPK FA in cancer patients remains largely unknown. The present thesis was comprehensively to examine association of PDPK FA expression with cancer progression and patient survival. Patients and Methods: PDPK FA expression in the resected tumors of 275 cancer patients, including 167 head and neck squamous cell carcinoma (HNSCC) patients, 74 colorectal cancer patients, and 34 esophageal cancer patients was analyzed by immunohistochemistry. Highly condensed nuclear PDPK FA exhibited in tumor cells was used as the major scoring parameter for positive PDPK FA expression. Survival analysis was used to analyze the data. Results: The frequency of positive PDPK FA expression was 41.3% (67/167) in HNSCC. Patients with positive PDPK FA showed poorer disease-free survival (DFS) and overall survival (OS) (P<0.001 for both). Cox multivariate regression analysis further established PDPK FA as the strongest independent prognosticator for cancer progression and patient survival in HNSCC (HR 3.063, 95% CI 1.884-4.981, P<0.001 for DFS and HR 4.192, 95% CI 2.396-7.332, P<0.001 for OS). Further, in the combination analysis with independent prognostic factor on the survival data, PDPK FA appeared to play a determinant, instructional and predominant role superior to the current powerful TNM staging system in prognostic prediction. Finally, logistic analysis showed that established PDPK FA is a very powerful prognostic indicator of response to adjuvant therapy in HNSCC (OR 12.581, 95% CI 4.807-32.932, P<0.001). Besides, we combined the other two different types of cancers (colorectal cancer and esophageal cancer) to analyze. The frequency of positive PDPK FA expression was 41.8% (115/275). Patients with positive PDPK FA showed poorer disease-free survival (DFS) and overall survival (OS) (P<0.001 for both). Cox multivariate regression analysis further established PDPK FA as the strongest independent prognosticator for cancer progression and patient survival (HR 3.980, 95% CI 2.658-5.960, P<0.001 for DFS and HR 5.815, 95% CI 3.649-9.267, P<0.001 for OS). Further, in the combination analysis with independent prognostic factor on the survival data, PDPK FA appeared to play a determinant, instructional and predominant role superior to the current powerful TNM staging system in prognostic prediction. Finally, logistic analysis showed that established PDPK FA is a very powerful prognostic indicator of response to adjuvant therapy (OR 11.911, 95% CI 5.465-25.958, P<0.001). Conclusion: In consistence with its multisubstrate/multifunctional PDPK nature essential for the development of highly malignant phenotypes, the present human study indicates that PDPK FA is a new signal transducing molecule for prediction of cancer progression and response to adjuvant therapy. Together with the previous molecular, cellular and animal studies, this thesis establishes PDPK FA as a new and common promising target for the strategic development of reliable and accessible prognostic and therapeutic modalities for more efficacious treatment in different types of cancers.