- 學位論文
探討小細胞肺癌組織中缺氧誘導因子-1a 之表現量與預後狀況之相關性
Expression of HIF-1a and its association with the prognosis in small cell lung cancer
摘要
缺氧對於腫瘤在血管新生、轉移及化學治療、免疫治療或放射治療的抗性是一個重要因素，也代表著不良的預後。缺氧會促發HIF-1a蛋白的聚積，此結果係由穩定此蛋白避免降解而非增加其m-RNA的轉錄或轉譯。然而，HIF-1a其半衰期很短不到五分鐘。在氧氣充足下，HIF-1a蛋白會持續生成，但也在同時經由26S proteasome pathway進行降解，因而維持一個低於偵測極限的恆定水平。當缺氧發生時，HIF-1a 就會大量聚積表現。在以往許多論文都曾報告過，HIF-1a 的大量表現與一些癌症如乳癌、口咽癌、子宮頸癌與非小細胞肺癌的不良預後有關。但仍未有HIF-1a表現與小細胞肺癌預後的相關研究。 研究設計為回溯性分析，以HIF-1a的免疫組織化學染色來評估43個小細胞肺癌病人組織並依表現程度來分組，進而以統計方法(Kaplan and Meier survival curve and Log-rank test)來分析HIF-1a的表現與病患的預後生存期。 結果顯示90.7%小細胞肺癌組織有HIF-1a的表現。病患的生存期反比於HIF-1a的表現 (高度表現，平均生存期16.5+1.75週，低度表現，平均生存期48.6+3.4週)。此外，小細胞肺癌的早期轉移與HIF-1a的高度表現亦有正相關。 相較於非小細胞肺癌，HIF-1a的表現在小細胞肺癌中更為顯著，就此可說明小細胞肺癌若無接受治療比非小細胞肺癌更為惡性且易早期遠處轉移。結論，如同以往的許多研究報告，越高度的HIF-1a表現代表越差的預後。在我們的報告中，若HIF-1a在小細胞肺癌中過度表現顯示有早期轉移的趨勢及較短的生存期。
並列摘要
Hypoxia is a key factor in tumor angiogenesis, metastasis and resistance to chemotherapy, immunotherapy, or radiotherapy that may indicate poor prognosis. Hypoxia may induce accumulation of hypoxia inducible factor-1a (HIF-1a), which is a result of stabilization of HIF-1a, not increase transcription or translation of its m-RNA. However, the half life of HIF-1a is short. (less than 5 minutes) Under nomoxic condition, HIF-1a is constitutively synthesized and degraded by 26S proteosome pathway at the same time, therefore, keeping the steady state level below the detectable limit. When hypoxia develops, HIF-1a is accumulated largely. Increased HIF-1a expression has been reported in many previous papers to be associated with poor prognosis in breast cancer, oropharyngeal cancer, cervical cancer and non-small cell lung cancer. There is not data showed the association between the HIF-1a expression and the prognosis of small cell lung cancer. This study is designed to examine the role of HIF-1a expression to influence the prognosis of small cell lung cancer. In this study, forty-three small cell lung cancer cases were stained by immunohistochemistry of HIF-1a and scored by the different level of HIF-1a expression. Further, analysis the HIF-1a expression and patient’s survival by Kaplan and Meier survival curve and log-rank test. The results showed that 90.7% small cell lung cancer expressed HIF-1a by immunostain and the level of HIF-1a overexpression was inversely related to survival time (high level : 16.5+1.7 weeks, low level : 48.6+3.4 weeks, P<0.001). Besides, the tumor expressed high HIF-1a level was significantly associated with earlier distant metastasis. Compare with non-small cell lung cancer, the expression of HIF-1a in small cell lung cancer was more predominate. It might explain why small cell lung cancer without treatment was more malignant and earlier metastasis. In conclusion, as same as many previous studies reported that the higher HIF-1a expression indicated a worse prognosis. In our study, the patient of small cell lung cancer with HIF-1a overexpression had a high potential to early metastasis and a short survival time.