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標題: | Heat Shock Factor 1於口腔鱗狀細胞癌中之表現 Expression of Heat Shock Factor 1 in oral squamous cell carcinoma |
作者: | Wen-Ren Lin 林文仁 |
指導教授: | 鄭世榮 |
共同指導教授: | 郭彥彬,江俊斌 |
關鍵字: | 熱休克轉錄因子1,口腔鱗狀細胞癌,口腔上皮變異, HSF1,oral squamous cell carcinoma,oral epithelial dysplasia, |
出版年 : | 2013 |
學位: | 碩士 |
摘要: | 中文摘要
背景 熱休克蛋白(heat shock proteins, 簡稱HSPs)扮演著伴護蛋白分子(molecular chaperones)的角色,藉由維持細胞內蛋白質的正常摺疊與恆定,這些熱休克蛋白保護細胞免於環境緊迫所造成的蛋白質結構性傷害,並對已受損害的蛋白質進行修復或水解,以恢復蛋白質正常的生理功能,維持蛋白質功能的平衡性。而熱休克轉錄因子1(Heat Shock Factor 1,簡稱HSF1),是一個82-k Da的轉錄因子,負責調節熱休克蛋白和其他逆境蛋白基因轉錄,引起熱休克反應的中樞。在一些熱休克的反應或是存在外在壓力下的環境,會強烈的活化這個轉錄因子的作用,以產生更多的熱休克蛋白幫助修復在惡劣環境中受到損害的一些蛋白質,好讓細胞得以在惡劣的環境中繼續存活下來。 腫瘤內的細胞,經常暴露在惡劣和變化迅速的微環境中。為了持續生長和發展,癌細胞必須能夠很有效率的適應這樣的微環境,就像前面所提及的生物體應付生存壓力時一樣,癌細胞也會發展出特定的機制來適應環境。許多研究都可以觀察到在不同的人類腫瘤中,如前列腺癌、肺癌、大腸癌、胰臟癌、子宮頸癌、膀胱癌及腦膜瘤等的表現量都有提高的情形。本研究欲探討HSF1於口腔癌病理組織中的表現量及與臨床各參數和存活時間的關係。 材料與方法 本研究利用免疫組織化學染色方法,探討HSF1於92例口腔鱗狀細胞癌(OSCC)、25例口腔上皮變異(OED)及35例正常口腔黏膜(NOM)中的表現,並以陽性染色指標Labeling index記錄其染色程度。利用卡方檢定(Chi-square test)、Kaplan-Meier 存活率方法及Cox proportional hazard regression model來分析HSF1的表現與口腔鱗狀細胞癌患者臨床病理參數及存活率之相關性,並試圖尋找影響存活時間的獨立預後因子。 結果 在正常口腔黏膜HSF1的平均陽性標記指數為12% (最低),口腔上皮變異組的平均陽性標記指數為34%,口腔癌組的平均陽性標記指數為54% (最高),從正常口腔黏膜、上皮變異至口腔癌的癌化過程,HSF1表現增加之情形已達統計意義(P < 0.001)。HSF1的表現和患者的腫瘤大小(T status)、淋巴結轉移與否(N status)、癌症臨床分期(Stage)有統計上相關。 各項臨床參數在Cox proportional hazard regression model分析中,單變數分析後發現,腫瘤大小、淋巴結轉移與否、腫瘤臨床分期及HSF1的陽性染色指標(LI)都與存活率有關;多變數分析腫瘤大小、淋巴結轉移與否及HSF1的陽性染色指標(LI)為影響存活時間的獨立因子(independent factor;p<0.05);HSF1陽性染色指標若>53%,影響病人存活的危險率(hazard ration)高達6.249倍(p=0.043)。 若以Kaplan-Meier plots來觀察臨床病理各項參數、HSF1的陽性染色指標與病人總存活時間(overall survival),經Log-Rank Test分析後,腫瘤大小、淋巴結轉移與否、腫瘤臨床分期均影響病人的存活時間,且達統計上之意義(p<0.05)。而本研究探討的HSF1的陽性染色指標(LI)若>53%,則明顯降低了口腔癌病人的存活率(p=0.044)。 結論 在本研究中,HSF1的陽性染色指標在口腔癌病理標本中的表現較高且具統計上意義,且與口腔細胞癌患者在臨床參數及存活時間有關。在口腔癌患者而言,HSF1的表現量較高者其存活時間較短;而HSF1在切片組織中的表現程度,或許可以做為口腔癌的預後指標(prognostic marker)。 Abstract Background HSPs function as molecular chaperones to restore protein homeostasis. Heat Shock Factor 1(HSF1) is an 82-k Da transcription factor that is strongly activated in response to heat shock and other forms of environmental and chemical stresses. HSF1 is responsible for expression of a large class of heat shock proteins, which protect cells from damage as a result of cellular insults, heat chock and oxidative stress. The tumor cell is usually exposed to the harsh environment. Heat Shock Factor 1(HSF1), master regulator of heat-shock proteins, facilitates the survival and proliferation of tumor cells under such conditions. Many types of highly malignant tumors express high levels of HSF1, including prostate, lung, colon, pancreas, cervix and meningioma. Our study shows that the over expression in OSCC and the correlation with the clinical, pathological parameters, and survival time. Materials and Methods Examined in this study were 92 specimens diagnosed as oral squamous cell carcinoma (OSCC) and 25 specimens of oral epithelial dysplasia (OED). 35 cases of normal oral mucosa (NOM) were also observed for comparison. With a HSF1 monoclonal antibody, immunohistochemistry (IHC) stain was performed for detecting expression of HSF1 in these tissue sections. The degree of positive staining was recorded and graded as labeling index (LI). Finally, the correlations between expression of HSF1, clinical and pathologic parameters, and the overall survival of OSCC patients were analyzed statistically via Chi-square test, Cox proportional hazard regression model, and Kaplan-Meier plots. Results The labeling index of HSF1 was significantly higher in OSCC specimens (p<0.001). The average LI of HSF1 in OSCC specimens was 54%. In OED specimens, the average LI was 34%. In NOM, the average LI was only 12%. Meanwhile, higher HSF1 LIs indicated larger tumor size (T3 and T4 status), nodal metastasis and later clinical stage (Stage 3 and stage 4). These results were all revealed with statistical significance (Chi-square test; p<0.05). As Cox proportional hazard regression model, the tumor size (T status), nodal metastasis (N status), clinical stage, and the LIs of HSF1 were statistically significant. Multivariate analysis revealed that tumor size (T status), nodal metastasis (N status) and the LIs of HSF1 were independent factors of patient survival (p<0.05). Kaplan-Meier survival analysis showed that patients had shorter survival time with advanced tumor sizes, nodal metastasis, later clinical staging, and high LIs of HSF1. Conclusions The expression of HSF1 was higher in OSCC specimen. The labeling index of HSF1 has strong correlation with several clinicopathological parameters and survival time. In OSCC patients, higher HSF1 expression seemed to indicate shorter overall survival. Judging from the above analysis, HSF1 is probably a potential prognostic factor of OSCC. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62663 |
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顯示於系所單位: | 臨床牙醫學研究所 |
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