鉀氯離子共同運輸蛋白是調控人體滲透壓平衡的主要決定因子之一。本實驗室先前一系列研究已發現鉀氯離子共同運輸蛋白在癌症進程上扮演許多重要角色。而本研究目的則是釐清鉀氯離子共同運輸蛋白在腫瘤生物學中的重要角色及調控機制。本研究包含四個部份。(一) 第四型鉀氯離子共同運輸蛋白(KCC4)表現量和癌細胞轉移能力的相關性。從雷射顯微切割技術加上即時定量系統，以及應用免疫螢光染色實驗所得到的結果，都證實轉移癌組織會表現大量的第四型鉀氯離子共同運輸蛋白，而有利於癌細胞的侵蝕性爬行及轉移。此外，第四型鉀氯離子共同運輸蛋白在轉移性癌組織中，和第一型類胰島素生長因子(IGF-1)及上皮細胞生長因子(EGF)有一共同表現的趨勢，顯示第四型鉀氯離子共同運輸蛋白在癌細胞的功能及表現可受到這二種生長因子的調節。(二) 探討第四型鉀氯離子共同運輸蛋白在癌細胞侵蝕的重要角色及其獨特調節機轉。利用卵巢癌及肺腺癌細胞株實驗模式中及配光學影像技術發現，第一型類胰島素生長因子及上皮細胞生長因子會促進第四型鉀氯離子共同運輸蛋白從細胞內胞器(如：內質網及高爾基氏體)運輸到侵蝕性癌細胞之前端細胞膜上；第四型鉀氯離子共同運輸蛋白於此處和細胞骨架結合蛋白(ezrin)相互作用以調控細胞骨架結構，進而促進癌細胞的侵蝕及轉移能力。(三) 以果蠅為活體實驗模式研究鉀氯離子共同運輸蛋白在上皮細胞發展的新穎功能。從基因學及分子生物學實驗得到的實驗結果顯示，果蠅的鉀氯離子共同運輸蛋白為胚胎發育過程的必需因子，而在神經系統活性及體內鹽份恆定方面扮演重要角色。此外，果蠅的鉀氯離子共同運輸蛋白對於果蠅的翅膀上皮細胞發育也很重要，主要藉由和上皮細胞中的細胞骨架蛋白(actin)結合而調控翅膀觸毛的生長。此研究結果可支持未來利用果蝇為活體模式進一步探討鉀氯離子共同運輸蛋白在腫瘤生物學上的其它新穎功能。(四) 探討鉀氯離子共同運輸對於癌細胞爬行的獨特調節機轉。我們探討鉀氯離子共同運輸活性是否對於上皮細胞生長因子引起的細胞骨架及細胞黏附(focal adhesions)的動態平衡有所影響，進而調控癌細胞的爬行活性。上皮細胞生長因子可能會調節KCC4和beta 1 integrin、ezrin、及focal adhesion kinase (FAK)之間的動態交互作用，進而影響爬行性癌細胞中細胞骨架重整過程。總結以上，此研究對於了解鉀氯離子共同運輸蛋白在癌細胞的侵蝕能力之角色及重要性將有很大的進展，並且提供基礎研究證據支持鉀氯離子共同運輸蛋白未來應用於臨床上癌症的診斷及治療。

The KCl cotransporter (KCC) is a major determinant of osmotic homeostasis and plays an important role in cancer development and progression. My thesis focuses on the emerging role for KCl cotransport in tumor biology and the novel mechanisms by which KCl cotransport regulates cancer malignant behaviors. My thesis includes four parts. (1) KCC4 expression is associated with cancer metastasis and clinical outcome. This part of study aims to investigate the contribution of individual KCC isoforms in cancer metastasis using cervical cancer and ovarian cancer as the model. The results indicate that metastatic cancer tissues express abundant KCC4 which benefits cancer cells in invasiveness. In the metastatic cancer tissues, KCC4 colocalizes with IGF-1 or EGF, indicating a likely in vivo stimulation of KCC4 function by growth factors. (2) Membrane trafficking of KCC4 is important for cancer cell invasion. Here I test the hypothesis that the regulation of specific KCC activation in cancer cells is a dynamic process which can be significantly upregulated by IGF-1 or EGF. The results indicate that IGF-1 and EGF stimulate the membrane recruitment of KCC4, in which KCC4 interacts with an actin-binding protein, ezrin, at lamellipodia. In addition to ion transport, KCC4 can function as a membrane scaffold to facilitate the modulation of cytoskeletal reorganization that is required for the invasive migration of cancer cells. (3) KCl cotransporter is an evolutionarily conserved assembly factor for actin-containing cellular protrusions. The novel functions of KCC in epithelial development were investigated using Drosophila melanogaster as a model. With the generation of KCC null mutants, it is suggested that fly KCC has essential role in the embryonic development and in the regulation of neural activity and salt homeostasis. Moreover, KCC is present in actin-bundle containing cellular protrusions of wing hairs and may play a role in the development of wing epithelium. (4) KCl cotransport is important for actin reorganization and focal adhesion dynamics during cancer cell migration. Here I test the hypothesis that KCl cotransport regulates cancer cell invasive migration is via the modulation of actin cytoskeleton and focal adhesions. The results suggest that KCl cotransport is necessary for actin reorganization and focal adhesion dynamics during cancer cell migration. Taken together, the results of my thesis provide the rationale for the clinical application of KCC as the therapeutic target and the prognostic biomarkers of metastatic cancers.

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