脯氨酸導引蛋白質激酶FA在腫瘤與間質相互作用和診斷腸胃癌病人結果之中的角色

Role of Proline-Directed Protein Kinase FA (PDPK FA) in Tumor-Stroma Interaction and Outcome of Gastrointestinal Cancer Patients

郭豪翔(Hao-Hsiang Kuo)

指導教授 ： 楊孝德

國立清華大學/生命科學院/分子與細胞生物研究所/碩士(2010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、轉移等是必備因子。然而，PDPK FA 在腫瘤與間質交互作用與作用機轉上的角色所知甚少而且需要進一步證實。本論文將分析新的訊號傳遞分子脯氨酸導引蛋白質激酶FA (PDPK FA)在腫瘤與間質相互作用中所扮演的角色並且檢測腸胃癌病人的結果是否與此分子有關聯性。
病人和方法：利用免疫組織染色法分析142位胃癌與43位大腸直腸癌病人外科切除的腫瘤切片中，PDPK FA的表現情形。腫瘤與間質細胞核具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：首先，我們證明過度表現PDPK FA的腫瘤細胞有趨勢性地使E-cadherin表現下降與Ｔwist表現上升，由此可知上皮細胞是經由上皮-間質轉化形成間葉細胞型態的腫瘤。第二點，PDPK FA表現的骨髓先驅幹細胞與間葉幹細胞在腫瘤間質中會以等比例的伴隨著CD68巨噬細胞或vimentin間葉細胞的出現 (P<0.001)，並且與間葉形態的腫瘤細胞透過造骨蛋白 (OPN) (P<0.001)、第六介白質(IL-6) (P<0.001)、變形生長因子 (TGF-β1)、血管內皮生長因子 (VEGF)、組織因子 (TF)網狀系統共同演化。在這情況下，PDPK FA 腫瘤間質共同演化與腸胃癌病人不良後果有顯著關聯 (P<0.001)。
結論：本論文建立 PDPK FA 在腸胃癌病人的結果中扮演著舉足輕重角色，並且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。此外，更說明了PDPK FA在腫瘤間質交互作用的角色。結合之前分子、細胞及動物的研究，本篇論文建立了PDPK FA為一種嶄新且傑出的指標，為了策略性地發展可信又有效的標靶，而這將對腸胃癌產生更有效的治療。

關鍵字

脯氨酸導引蛋白質激酶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 role of PDPK FA in tumor microenvironment remains largely unknown and needs to be further established. Our purpose of this thesis was to analyze the association of PDPK FA expression with the modulation of the interaction of tumor and stroma and relation to survival of gastrointestinal (GI) cancer patients.

Patients and Methods: PDPK FA expression in the resected tumors of 142 gastric cancer and 43 colorectal cancer patients was analyzed by immunohistochemistry. Expression pattern of highly condensed nuclear PDPK FA exhibited in tumor and stromal cells were used as the major parameter for positive PDPK FA expression. Survival analysis was used to analyze the data.

Results: First, we demonstrated that overexpressed nuclear PDPK FA was associated with the downregulation of E-cadherin, and therefore might promote the process of epithelial-mesenchymal transition (EMT). Second, PDPK FA expression with HSPC and/or MSC in tumor-stroma hierarchically associated with equal or more than one hotspot of CD68 macrophages and/or vimentin mesenchymal cells (P<0.001), and therefore had co-evolution with mesenchymal tumor cells through OPN (P<0.001), IL-6 (P<0.001), TGF-β1, VEGF, and TF networks. Under this circumstance, GI cancer patients who had tumor-stroma co-evolution of PDPK FA tend to be poor outcome (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 GI cancer patient outcome. Furthermore, it elucidates the probable mechanism that PDPK FA has the role in tumor-stroma interaction. Together with the previous molecular, cellular, animal, and clinical studies, this thesis establishes PDPK FA as a new and common promising target for the strategic development of reliable and accessible therapeutic modalities for more efficacious treatment in GI cancer.

並列關鍵字

PDPK FA ； GSK-3alpha ； gastrointestinal cancer ； EMT ； tumor-stroma ； cytokine network

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