上皮-間質細胞轉換過程(epithelial-mesenchymal transition)為一個調控上皮細胞可塑性的重要機制，伴隨在許多種惡性腫瘤轉移進程中。本博士論文研究則是去探討上皮-間質細胞轉換過程與子宮頸癌惡性進程之臨床相關性，及探討其中所參與的新穎訊息調控機轉。本論文架構包含三個部分。(一) Snail轉錄因子的過量入核表現參與在上皮生長因子所調控的上皮-間質細胞轉換過程。將上皮生長因子EGF慢性刺激群聚生長的子宮頸癌細胞，會導致細胞型態延長、分離散佈，且增加細胞侵犯性。此訊息傳遞是透過去活化GSK-3beta，穩定Snail轉錄因子蛋白質於細胞核的表現，導致上皮-間質細胞轉變過程。以免疫螢光染色實驗檢驗子宮頸癌組織，證實上皮標誌E-cadherin隨著轉移癌組織表現逐漸下降，而間質標誌vimentin表現逐漸增加，此過程伴隨著上皮細胞生長因子受體過度表現，以及Snail轉錄因子表現增加且聚集在細胞核。建立Snail轉錄因子過量表現的癌細胞，其細胞分散程度與侵犯能力增加。利用雷射顯微切割技術加上即時定量系統，發現與無淋巴轉移病人相比，腹腔淋巴轉移病人原位癌細胞的Snail轉錄因子表現量增加。總結研究顯示：Snail轉錄因子的過量表現會增加癌細胞的侵蝕與轉移能力。(二) 纖維連結蛋白fibronectin與細胞外基質結合受體 alpha5beta1 integrin可調節上皮生長因子所調控的上皮-間質細胞轉換過程。使用不同種integrin功能拮抗性抗體與細胞外基質，發現纖維連結蛋白與基質結合受體alpha5beta1 integrin透過調節Snail轉錄因子細胞核內過量表現，而增強上皮生長因子所誘導的子宮頸癌細胞上皮-間質細胞轉變過程。(三) 探討蛋白激酶PKC-delta 與Snail轉錄因子的相互調控以及上皮生長因子所誘導的上皮-間質細胞轉換過程之影響。此研究著重探討是否PKC-delta可能參與調控子宮頸癌的上皮-間質細胞轉換過程。組織免疫螢光染色顯示，細胞核PKC-delta表現與共存的少量E-cadherin表現存在於部分癌腫瘤組織的中央區域；檢驗同源病人的正常與癌組織蛋白量，發現PKC-delta和Snail轉錄因子的過量表現有正相關趨勢。抑制或促進PKC-delta的活性或是抑制PKC-delta的表現，皆會影響子宮頸癌細胞內源性的Snail表現量。以上皮生長因子來慢性誘導子宮頸癌細胞進行上皮-間質細胞轉換過程，酪酸根磷酸化態PKC-delta出現在訊息傳遞時程早期，且分布在細胞質特定區域；但抑制PKC-delta的表現不會反轉上皮生長因子所誘導的上皮-間質細胞轉換的分子蛋白表現。總結本研究發現，此結果顯示PKC-delta可能與上皮-間質細胞轉換過程相關，仍須進一步釐清。總結以上結果，本論文提供上皮-間質細胞轉換過程的臨床重要性，以及上皮生長因子EGF、基質結合受體alpha5beta1 integrin、以及蛋白激酶PKC-delta的扮演角色，顯示Snail轉錄因子在子宮頸癌細胞的侵襲能力有重大影響。提供臨床與基礎研究證據支持Snail轉錄因子於未來應用於臨床癌症的診斷與治療。

Epithelial-mesenchymal transition (EMT) is one of the mechanisms controlling epithelial plasticity and involved in the cancer malignant progression. Snail is important transcription repressor for E-cadherin expression. My thesis focuses on the clinical relevance of epithelial-mesenchymal transition and the identification of novel regulatory signaling mechanisms in the stepwise progression of cervical carcinoma. There are three parts included in my thesis. (1) Up-regulation of Snail is involved in EGF-mediated mesenchymal transition of cervical cancer. This part of study aims to investigate the effects of EGF on the EMT program of cervical cancer cells. The results indicate that EMT program is associated with the malignant cancer progression with concomitant EGFR overexpression, E-cadherin downregulation, vimentin and Snail upregulation. Chronic stimulation of EGF in cervical cancer cells can initiate EMT program through upregulation of Snail transcription factor. Our results suggest that Snail overexpression is important for cell plasticity, cell invasiveness, and distant metastasis. (2) alpha5beta1 integrin and fibronectin modulate EGF-mediated EMT. Using various functional blocking integrin antibodies and ECM coating conditions, we identified that alpha5beta1 integrin and its extracellular matrix fibronectin can augment EGF-mediated mesenchymal transition through modulation of nuclear Snail protein accumulation in cervical carcinoma cells. (3) Characterization of the role of PKC-delta in the regulation of Snail and EGF-mediated EMT. Here, I test the involvement of PKC-delta in the regulation of EMT in cervical cancer. Immunofluorescent staining shows an association between nuclear PKC-delta accumulation and E-cadherin loss in the central tumor mass in some cases of cancer tissue. In addition, there is an association of concurrent overexpression of PKC-delta and Snail in matched cancer tissue and cultured cervical cancer cells, suggesting PKC-delta and Snail are in the same signaling axis. Upon chronic EGF stimulation, tyrosine-311 phosphorylated PKC-delta occurs in prior to GSK-3beta inactivation and Snail upregulation. However, depletion of PKC-delta expression by siRNA does not alleviate EGF-mediated EMT-related molecular changes. In conclusion, this thesis provides a new insight into the important regulatory signal related to Snail transcription factor in the mesenchymal transition of cervical carcinoma.

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