人類乳突瘤病毒對鼻咽癌致癌及預後相關性之探討

• Main Authors: 魏瑄貝, Wei, Hsuan-Pei
• Other Authors: 分子醫學研究所, 蘇五洲, Su, Wu-Chou
• Format: Thesis
• Language: English
• Published: 2011
• Subjects: Arctic
• Online Access: http://ir.lib.ncku.edu.tw/handle/987654321/114170; http://ir.lib.ncku.edu.tw/bitstream/987654321/114170/-1/index.html

鼻咽癌好發於北極、東/北非、中國南部、中亞、東南亞，包括臺灣。已知的致病因素包含遺傳、環境及EB病毒等。人類乳突瘤病毒，尤其是高危型病毒(high- risk HPV)，是引發子宮頸癌的主因，主要的致癌機轉是病毒的E6、E7基因插入宿主基因組中，引發基因組的不穩定性並抑制細胞分裂的調控機轉，使得細胞轉型。除子宮頸癌，先前亦有研究顯示，在鼻咽癌患者的病理組織中也可偵測到人類乳突瘤病毒的存在，然而之前的研究由於技術限制及樣本取得等因素，對於人類乳突瘤病毒與鼻咽癌好發程度間之相關性看法仍相當分歧，例如單以聚合?連鎖反應檢測則無法區分病毒是位於癌細胞或周邊之正常組織中。因此，本篇論文一方面以人類乳突瘤病毒基因晶片偵測鼻咽癌病理組織及正常鼻咽組織中之人類乳突瘤病毒並加以分型，進而探討人類乳突瘤病毒存在與否與鼻咽癌發生及預後之間的相關性。另一方面，我們也以原位雜交技術偵測高危型人類乳突瘤病毒在鼻咽癌組織中的表現情形，並探討其與鼻咽癌病患臨床資料的關聯。基因晶片的研究結果顯示，人類乳突瘤病毒基因在鼻咽癌病理樣本及正常鼻咽組織的陽性偵測率約略相當。而高危型人類乳突瘤病毒存在與否，與患者之性別、WHO分型及預後等皆無明顯關聯。原位雜交實驗的結果則顯示，高危型人類乳突瘤病毒大多存在於鼻咽癌細胞質或細胞核週邊，與已知高危型人類乳突瘤病毒相關之子宮頸癌或口咽癌細胞的細胞核內染色明顯不同。部份高危型人類乳突瘤病毒偵測為陽性的鼻咽癌組織，其相對應之轉移性淋巴結內之腫瘤細胞亦無法偵測到高危險性人類乳突瘤病毒的存在。此外，基因晶片以及原位雜交實驗的結果都顯示，帶有高危型人類乳突瘤病毒之鼻咽癌病患其平均年齡較未帶有高危型人類乳突瘤病毒之鼻咽癌病患要來得高，此與高危型人類乳突瘤病毒相關的口咽癌病患的平均年齡較低有明顯不同。因此，本研究提供了較全面的證據，顯示人類乳突瘤病毒對鼻咽癌而言可能並非重要的病毒性致癌因子。 Nasopharyngeal carcinoma (NPC) a head and neck neoplasm derived from epithelium of nasopharynx is endemic in the Arctic the Middle East/North Africa southern China the Middle/ Southeast Asia including Taiwan Various risk factors are involved in carcinogenesis of NPC such as genetic environment and viral (Epstein-Barr virus) factors On the other hand human papillomavirus (HPV) especially high-risk HPVs play a crucial role in cervical cancer development The HPV oncogenesis mainly due to the insertion of E6 and E7 genes into host genomes leading to instability of host genomes inhibition of cell cycle regulation and consequently cell transformation Previous investigations indicated that HPV genomes had been detected not only in cervical cancer but also in NPC specimens However while studies showed that HPV genome can be detected in NPC specimens the correlations between HPV and NPC occurrence are still elusive For instance even if the PCR results suggested that the HPV genomes exist in a specimen it can not distinguish whether the HPV genome is located in NPC cells or in the surrounding normal cells Therefore to clarify these issues we first studied the prevalence of HPV genomes in 43 NPC and 40 control nasopharyngeal specimens using commercial HPV genechips In addition we performed high-risk HPV in situ hybridization to localize high-risk HPV genomes in another 46 archival NPC specimens Correlation between tumor HPV status and clinical parameters of these patients was subsequently analyzed We found that HPV cab be equally detected in both NPC (34 9% 15/43) and control (42 5% 17/40) specimens Most (89 5% 17/19) of the high risk HPV-positive NPC neoplasm showed an unique cytoplasm/perinuclear staining pattern which is different from the dot/punctate nuclear staining pattern indicating HPV DNA integration as in cervical cancers Besides high-risk HPVs were not always clonally proliferated in NPC cells during the process of lymph node metastasis Also tumor high risk HPV status did not correlate with gender WHO subtype or prognosis of these patients Patients whose tumor had high-risk HPVs are elder than those without HPVs which is also epidemiologically different from HPV-related oropharyngeal cancers Taken together our study did not support that high risk HPV as a crucial viral carcinogenic factor of NPC in Taiwan