臺灣博碩士論文加值系統

口腔癌是頭部及頸部腫瘤中最常見的一種癌症，其主要的特徵是不容易診斷及低存活率。血管內皮生長因子-C (Vascular endothelial growth factor-C; VEGF-C) 被指出與淋巴管新生及癌症的轉移有關。而WNT1-inducible signaling pathway protein-1 (WISP)-1/CCN4是一種細胞間質蛋白為CCN家族成員，並參與在許多細胞生理功能之中，在之前的研究也證明WISP-1可促進口腔癌轉移及血管新生作用，然而WISP-1與VEGF-C的表現及淋巴管新生作用並不清楚。
本論文的研究發現WISP-1與VEGF-C的表現與口腔癌的惡性程度呈正相關，而使用淋巴管內皮細胞的實驗也發現：WISP-1刺激口腔癌後的培養液可增加淋巴管內皮細胞的管柱形成及移行能力，本論文也發現WISP-1所增加VEGF-C表現是經由integrin αvβ3/integrin-linked kinase (ILK)/Akt訊息傳遞路徑進而抑制microRNA-300 (miR-300)而來。這些發現可能有助於去理解轉移的機制和發展口腔癌更有效的治療方式。

Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by a poor prognosis and a low survival rate. Vascular endothelial growth factor-C (VEGF-C) has been implicated in lymphangiogenesis and is correlated with cancer metastasis. WNT1-inducible signaling pathway protein-1 (WISP)-1/CCN4 is an extracellular matrix-related protein that belongs to the CCN family and stimulates many biological functions. Previous studies showed that WISP-1 plays an important role in OSCC migration and angiogenesis. However, the effect of WISP-1 on VEGF-C regulation and lymphangiogenesis in OSCC is poorly understood. Here, we showed a correlation between WISP-1 and VEGF-C in tissue specimens from patients with OSCC. To examine the lymphangiogenic effect of WISP-1, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. The results showed that conditioned media from WISP-1–treated OSCC cells promoted tube formation and cell migration in LECs. We also found that WISP-1–induced VEGF-C is mediated via the integrin αvβ3/integrin-linked kinase (ILK)/Akt signaling pathway. In addition, the expression of microRNA-300 (miR-300) was inhibited by WISP-1 via the integrin αvβ3/ILK/Akt cascade. Collectively, these results reveal the detailed mechanism by which WISP-1 promotes lymphangiogenesis via upregulation of VEGF-C expression in OSCC. Therefore, WISP-1 could serve as therapeutic target to prevent metastasis and lymphangiogenesis in OSCC.

中文摘要 II
Abstract III
圖 目 錄 VI
第一章 緒論 1
第一節 人類口腔鱗狀細胞癌(Human oral squamous cell carcinoma) 1
第二節 轉移 (Metastasis) 4
第三節 淋巴管新生(Lymphangiogenesis)及血管內皮生長因子 (Vascular endothelial growth factor ; VEGF) 6
第四節 Wnt-inducible secreted protein-1 (WISP)-1 9
第五節 MicroRNAs (miRNAs) 11
第二章 研究動機 26
第一節 研究目的 26
第二節 研究假設 28
第三章 材料與方法 29
第一節 實驗材料 29
第二節 實驗方法 33
第四章 研究結果 45
第五章 討 論 81
第六章 結 論 84
參考文獻 86
附錄一：縮寫對照表 91
附錄二：發表期刊抽印本 92

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