口腔癌是一種具侵襲性的惡性腫瘤，常伴隨著很高的局部復發率及不佳的預後。這篇論文主要是從臨床觀察到分子生物上的表現以及調控的機轉來分析口腔癌侵襲的行為。
局部晚期的口腔癌最主要的治療方式為手術治療，並輔以術後的放射治療。但是口腔癌的侵襲性加上手術後組織解剖上的變化跟淋巴血管引流的改變，讓術後輔助的放射治療非常難以設計。已經有一些非預期跟致死的復發在術後輔助的強度調控放射治療上被注意到。在第一章裡，我們從接受手術後強度調控放射治療的頰膜癌病人上分析復發模式跟相關臨床病理因子。我們發現一開始就有咀嚼肌間隙(masticator space)侵犯是影響復發最重要的因素。因此在設計術後的放射治療應該不只考量手術的範圍，也應該把復發的位置跟模式給考量進去。
肝癌衍生因子(HDGF)參與許多癌化的過程，也在多種的癌症中被視為影響預後的重要因子。在第二章中，我們探討HDGF在口腔癌癌化的角色。我們利用重組腺相關病毒載體(recombinant adenovirus vector)來調節HDGF的濃度，並進一步利用免疫墨點法、腫瘤侵襲試驗(invasion assay)，群落形成試驗(colony formation assay)來分析HDGF對腫瘤細胞行為的影響。同時利用免疫組織化學法的組織列陣來分析術後的病理檢體跟HDGF的表現以及其臨床病理因子的關係。
血管新生是腫瘤生長跟轉移所必需的，同時跟血管新生因子還有反血管新生因子的平衡有關。在血管新生因子中，血管新生因子(VEGF)最為重要。在第二章中，HDGF的表現跟VEGF的表現呈現正相關，並跟口腔癌的病人預後有很強的相關性。HDGF被認為可以調控VEGF的上游基因或是VEGF的啟動子。在第三章，我們發了一個新的路徑，在常氧的狀態下，HDGF經由Nucleolin接合後，會活化AKT/HIF-1α 跟 NFκB路徑，進而增加VEGF的表現。
總而言之，在口腔癌的癌化跟血管新生的過程中，HDGF的表現扮演很重要的角色。HDGF的表現不僅跟腫瘤的侵襲性、病人的預後還跟VEGF的調控都息息相關。

Oral cancer is aggressive cancer with high locoregional recurrence rates and poor prognosis. The purpose of this dissertation is to analyze the aggressive behavior of oral cancer form the clinical observation to the molecular expression and regulatory mechanism.
The treatment strategy for locally advanced oral cancer is surgery followed by post-operative radiotherapy. The aggressive behavior of oral cancer and the change of anatomic boundaries and lymphovascular drainage after surgery make the design of optimal radiotherapy very challenging. Some unexpected and fetal recurrences have been observed after post-operative intensity-modulated radiotherapy (IMRT). The aim of Chapter 1 is to analyze failure patterns and clinicopathologic prognostic factors in patients with locally advanced buccal cancer after post-operative IMRT. The initial masticator space involvement is revealed as the key factor for disease recurrence. Post-operative IMRT should not include the surgical beds alone, rather should be based on the potential patterns of spread failure
Hepatoma-derived growth factor (HDGF) participates in oncogenic progression and represents a prognostic factor in several types of cancer. Chapter 2 aimed to elucidate the role of HDGF during oral tumorigenesis. HDGF expression and the tumorigenic behaviors in human oral cell lines were investigated by immunoblotting, invasion and colony formation assays. Recombinant adenovirus vectors were employed to modulate the HDGF level in oral cancer cells. Immunohistochemical analysis using tissue microarray (TMA) consisting of surgically resected samples was performed to delineate the correlation between HDGF expression and clinic-pathological parameters.
Angiogenesis is essential for invasive tumor growth and metastasis through perturbing the balance of proangiogenic and antiangiogenic factors. Among the proangiogenic factors, vascular endothelial growth factor (VEGF) is the principal player. HDGF can also stimulate angiogenesis directly and induce VEGF releasing. In Chapter 2, HDGF expression was correlated with VEGF expression and led to the poor prognosis of the oral cancer patient. It is considered that HDGF might regulate the VEGF upstream genes or the VEGF promoters. A new pathway that HDGF activated AKT/HIF-1α and NFκB and then increased VEGF expression through nucleolin binding in a normoxic condition was disclosed in Chapter 3.
In summary, HDGF expression plays an important role in tumorigenesis and angiogenesis of oral cancer, which is associated with the aggressive tumor behavior, poor prognosis, and regulation of VEGF.

Contents
論文審定書 + i
誌謝 + ii
Abstract + iii
Chinese abstract + iii
English abstract + iv
Introduction + 1
Chapter 1: Patterns of failure after postoperative intensity-modulated radiotherapy for locally advanced buccal cancer: Initial masticator space involvement is the key factor of recurrence + 4
Backgrounds + 5
Materials and Methods + 6
Results + 11
Discussion + 17
Conclusion + 21
Tables + 22
Figures + 27
Supplementary materials + 28
Supplementary Table 1. + 28
Supplementary Figure 1. + 30
Chapter 2: The expression and prognostic significance of hepatoma-derived growth factor in oral cancer + 31
Backgrounds + 32
Materials and Methods + 34
Results + 41
Discussion + 45
Conclusion + 48
Tables + 49
Figures + 54
Chapter 3: Hepatoma-derived growth factor regulates VEGF expression via activation of HIF-1α signaling in oral cancer cells + 61
Backgrounds + 62
Materials and Methods + 64
Results + 66
Discussion + 69
Conclusion + 71
Figures + 72
References + 78
Appendix + 84
Publication + 84

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