鉀氯離子共同運輸體蛋白家族（KCC）在細胞中的主要功能是負責電中性的鉀氯離子共同運輸，並在不同細胞生理功能中扮演重要角色，如細胞體積調節、上皮細胞間的離子運輸、與調控細胞內氯離子濃度。在哺乳動物中已經有四種同型異構物被發現，其中鉀氯離子共同運輸體蛋白KCC1, KCC3與KCC4是廣泛性地分佈在各種不同組織中，然而鉀氯離子共同運輸體蛋白KCC2則是專一性表現在神經組織。本實驗室先前的研究初步顯示細胞體積調節機制可能在腫瘤的發生與進程中扮演重要角色。本研究證實癌症細胞的生長與侵蝕能力與調控離子與細胞滲透壓平衡的重要分子-鉀氯離子共同運輸體蛋白息息相關。在子宮頸癌細胞表現 鉀氯離子共同運輸體蛋白缺失功能的突變株會降低細胞侵蝕能力的現象與細胞中的細胞黏著因子 脉v刍3 與 脉6刍4 integrin 的表現量下降，並伴隨細胞外基質分解蛋白MMP2與MMP9的表現與活性的降低。在免疫缺失老鼠的腫瘤生長模式中發現子宮頸癌細胞表現鉀氯離子共同運輸體蛋白缺失功能的突變株能抑制腫瘤的生長結果，也確定鉀氯離子共同運輸體蛋白在促進子宮頸癌細胞的生長與侵蝕能力的必要角色。此外，藉第一型類胰島素生長因子（IGF-1）刺激而導致的鉀氯離子共同運輸體蛋白活化，證實在與促進婦科腫瘤的生長與擴散相關的第一型類胰島素生長因子的訊息調控中扮演重要角色。進一步研究發現，鉀氯離子共同運輸體蛋白KCC3的過度表現會抑制E-cadherin的基因轉錄表現並促進刍-catenin的蛋白質降解過程，藉由抑制E-cadherin/刍-catenin complex促進癌細胞的上皮細胞—間質細胞轉化過程，因此刺激腫瘤發生的進程。因此，抑制鉀氯離子共同運輸功能或許可以作為預防或延緩婦癌發展的治療方針。

The KCl cotransporter family (KCC) is responsible for electroneutral K-Cl co-transportation and plays important roles in cell volume regulation, transepithelial transport, and in the regulation of intracellular chloride concentration ([Cl-]i). Of the four mammalian KCl cotransporters, KCC1, KCC3 and KCC4 are widely expressed, whereas KCC2 is neuron specific. Our previous studies have begun to emerge the important roles of KCl cotransporters in tumor development and progression. In this thesis, we first demonstrated that the growth and invasion of cervical cancer cells are strongly linked the expression and activity of the KCl cotransporter (KCC). Reduced cellular invasiveness in loss-of-function KCC mutant cervical cancer cells is in parallel by reduced expression of 脉v刍3 and 脉6刍4 integrins, accompanied by decreased activity of matrix metalloproteinase 2 and 9. Inhibition of tumor growth in severe combined immunodeficiency (SCID) mice confirms the crucial role of KCC in promoting cervical cancer growth and invasion. In addition, KCC activation by insulin-like growth factor 1 (IGF-1) stimulation plays an important role in IGF-1 signaling to promote the growth and spread of gynecological cancers. Furthermore, overexpression of KCC3 in cervical cancer cells downregulates E-cadherin/刍-catenin complex formation by inhibiting transcription of E-cadherin gene and accelerating proteosome-dependent degradation of 刍-catenin protein. The disruption of E-cadherin/刍-catenin complex formation promotes EMT, thereby stimulating tumor progression. These evidences suggest that KCC may aid the invasive biology of cancer cells through new features of KCC function. Thus, blockade of KCl cotransport may be a useful therapeutic adjunctive strategy to retard or prevent gynecological cancer development and progression.

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