脯氨酸導引蛋白質激酶FA在肺癌病人的存活及預後之關鍵性角色

Prognostic Role of Proline-Directed Protein Kinase FA (PDPK FA) in Progression and Patient Survival of Non-small Cell Lung Cancer (NSCLC)

張心慈(Hsin-tzu Chang)

指導教授 ： 楊孝德講座教授

國立清華大學/生命科學院/分子與細胞生物研究所/碩士(2006年)

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、轉移等是最有潛力且最致命的因子之一，然而，PDPK FA 在癌症病人的預後角色上所知甚少，本研究將完整地系統性探討肺癌病人在開刀後，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156位肝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陽性表現的主要評值依據。所得資料主要是利用醫學統計進行存活分析。

結果
在肺癌病人中，PDPK FA陽性表現的比率是51% (80/156)，這些PDPK FA陽性表現的病人很明顯地呈現較差的預後，如較易復發、轉移和死亡。克氏多變項比例風險模式進一步建立PDPK FA在肺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 (肺癌復發風險比為5.438、死亡風險比為8.106，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不好的預後狀況。最後，用線性回歸模式分析，顯示以建立的PDPK FA在肺癌開刀後接受輔助性治療的反應是一非常強的訊號分子，PDPK FA陰性表現的病人接受輔助性治療的勝算比為11.190，是具有顯著意義的(P=0.001)。

結論
本論文建立PDPK FA在原發性肺癌經外科切除後預後的重要性，此結果和過去研究發現PDPK FA在促進癌快速惡化的致命性角色一致，PDPK FA是個共通的訊號傳遞分子預測癌症惡化和病人存活。綜言之，PDPK FA在高度侵犯性肺癌病人開完刀後預後的預測與治療上是個全新、可矯正的訊號傳遞標的分子。

關鍵字

肺癌 ； 脯氨酸導引蛋白質激酶 ； 預後 ； 存活率

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 study was comprehensively to examine association of PDPK FA expression with progression and patient survival of non-small cell lung cancer (NSCLC).

PATIENTS and METHODS:
PDPK FA expression in the resective tumors of 156 NSCLC patients was analyzed by immunohistochemistry. Highly condensed nuclear PDPK FA associated with 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 51% (80/156) in NSCLC. 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 progression and patient survival of NSCLC (HR 5.438, 95% CI 3.436-8.608 for DFS, P<0.001; HR 8.106, 95% CI 4.741-13.859 for OS, P<0.001). In the combination analysis with independent prognostic factor on the survival data, PDPK FA further appeared to play a determinant, instructional and predominant role superior to the current powerful TNM staging system in prognostic prediction. At last, the logistic analysis showed that established PDPK FA is a very powerful prognostic indicator of response to adjuvant therapy in the NSCLC patients (OR 11.190, 95% CI 2.701-46.367, 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, the thesis establishes PDPK FA as a new promising target for the strategic development of reliable and accessible prognostic and therapeutic modalities for more efficacious treatment of NSCLC.

並列關鍵字

non-small cell lung cancer ； PDPK FA ； prognosis ； survival

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