鼻咽癌好發於東南亞一帶，台灣亦是鼻咽癌的好發地區之一。鼻咽癌和EB病毒的密切關聯性，早已為人所熟知。鼻咽癌的主要治療是放射治療，或是併用化學治療。雖然近年來由於放射治療的改進及化學藥物的合併使用，對鼻咽癌的局部控制有相當長足的進步，但對於局部復發，特別是屬於局部復發晚期的病患，不論是再次放射治療〈或併用化學治療〉、手術治療〈或併用其他療法〉，病人長期存活率均不佳。因此，我們對於鼻咽癌細胞如何產生放射線治療或是化學治療的抗性，必須有更深入的了解，方能設計出更有效的治療方法。在本論文中，我們嚐試探討兩個與鼻咽癌治療相關的重要問題：第一、鼻咽癌的局部復發，到底是來自於原發腫瘤中對放射治療產生抗性的細胞，或者是另一個原發腫瘤(second primary)，目前仍不清楚。如果復發腫瘤是來自於原發腫瘤中對放射治療產生抗性的細胞，則鼻咽癌治療的研究方向應著重於如何早期偵測復發並加以治療；或是加強最初的治療方式(例如brachytherapy、cyberknief、手術、加重化學治療、提高放射劑量或併用radiosensitizer等等)，來除去這些具有治療抗性的細胞；如果復發腫瘤是另一個原發腫瘤，則我們的研究應著重於預防第二原發腫瘤的發生。第二、EB病毒所表現的LMP1蛋白質能夠誘發細胞的三個重要訊息傳遞途徑，分別是NFκB、AP-1以及JAK/STAT路徑。研究顯示，LMP1蛋白質的表現與否可能與鼻咽癌病患接受放射線治療的預後有關。然而，這三個訊息傳遞途徑在真正鼻咽癌組織中的表現型態為何？其組織表現型態是否與鼻咽癌病患接受放射線治療的預後有關？至今仍未有文獻探討。據此，在本論文中，針對第一個問題，藉由比較8例病患原發腫瘤和復發腫瘤所含的EB病毒基因的多樣性標記，我們的研究證據顯示，治療後三年內復發的鼻咽癌，極有可能是由原發腫瘤中具有治療抗性的殘存細胞發展而來，而較不可能是第二原發腫瘤。其次，針對第二個問題，我們發現EB病毒 LMP1蛋白質所引發的細胞三個訊息傳遞途徑，AP-1 (c-jun)以及STAT3、STAT5在超過半數以上的鼻咽癌組織中，具有明顯的細胞核染色型態，此顯示AP-1以及STAT3、STAT5在大多數鼻咽癌組織中有持續活化(constitutive activation)的情形；此外，鼻咽癌組織中LMP1蛋白質的表現，也和AP-1或是STAT3、STAT5的持續活化有統計學上的相關性。有趣的是，我們發現，鼻咽切片中AP-1或是STAT3/STAT5為持續活化型態的病患，其治療的預後較佳。此結果暗示著LMP1蛋白質可能藉由調控其下游訊息傳遞路徑的活化狀態，進而影響鼻咽癌細胞對放射治療的感受性。其詳細的調控機制，有待進一步探討。

　　Nasopharyngeal carcinoma (NPC) is endemic in certain Southeastern Asia area, including Taiwan. NPC is well known for its radio- and chemo-sensitivity. Although a high local control rate can be achieved by radiotherapy (R/T) alone in early staged patients, a substantial portion of advanced staged patients failed in treatment despite combining usage of chemotherapy in addition to radiotherapy. Treatment of late-staged local relapse is generally disappointing either by re-irradiation and/or surgery. Therefore, knowing the mechanisms that leads to chemo-radio-resistance would provide us a better chance to cope with this disease.
　　This study deals with two important problems on therapeutic aspects of NPC. Firstly, whether the recurrent NPC derives from the proliferation of radiotherapy-resistant residual tumor cells, or by the emergence of another tumor cell clone is still not known. If the recurrent tumor derives from a resistant primary-tumor cell clone, early detection of recurrence will be mandatory to achieve effective salvage treatment. Besides, adjuvant therapies (such as brachytherapy, cyberknief, operation, chemotherapy, elevated radiotherapy dose, radiosensitizer..etc.) must be taken to eradicate these resistant cells. On the other hand, if the recurrence is caused by another different cell clone, strategies that are able to prevent the emergence of new tumor clones would be particularly important. Secondly, Epstein-Barr virus (EBV) is implicated as one of the etiologies of NPC. And latent membrane protein 1 (LMP1) is thought to be the major oncogenic protein of EBV in NPC. It is well established that LMP1 can activate three important cellular signaling pathways --AP-1, NFκB and JAK/STAT. Since these pathways are critical in determining cellular responses to different external stimuli, it is reasonable to hypothesize that LMP1 might modulate radio-response of NPC cells through these downstream signaling pathways. However, the expression patterns and prognostic significance of these pathways in NPC tissues have not been fully explored.
　　In the first part of this study, by comparing the clonal relationship of EBV contained in 8 paired primary and recurrent NPC, we concluded that for NPC most, if not all, relapses that occurred within three years arose from residual tumor cells that resisted radiotherapy. Early detection of recurrence and adjuvant therapies capable of eradicating resistant cells should be considered as first priority in treatment of NPC. In the second part of this study, by using immunohistochemical methods, we demonstrated that two of the LMP1-activating cellular pathways, AP-1 and STAT3/STAT5, were constitutively activated in most of the NPC cases. In NPC tissues, expression of LMP1 protein also correlates with the activation status of AP-1, STAT3 and STAT5. Interestingly, patients who have constitutive activation of AP-1, or STAT3/STAT5 on their biopsy specimens significantly have better prognosis after radiotherapy. These results suggest that LMP1 may influence radio-sensitivity of NPC cells by modulating the activation status of these pathways. The detailed mechanism warrants further investigation.

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