臺灣博碩士論文加值系統

腎上腺皮質癌 (adrenocortical carcinome；ACC) 為一罕見卻極為惡性之腫瘤，其中以glucocorticoids過度分泌引發Cushing’s syndrome之ACC最為惡性。Mitotane 為臨床上Cushing’s syndrome與ACC輔助性治療之用藥，其專一性作用於腎上腺皮質，干擾steroidogenesis；同時亦具有抑制腫瘤生長之功能。儘管相關機制尚未明確，近年來累積之文獻指出，mitotane確實可降低ACC轉移機率、提升ACC病患存活率。
本論文研究方向即利用人類腎上腺皮質癌NCI-H295細胞株探討mitotane之作用機轉。Mitotane (10 – 40 M) 在未引發細胞死亡下抑制cortisol基礎與ACTH (1, 100 nM)、FK (1, 10 M)、8-Br-cAMP (10, 100 M) 所誘發之cortisol釋放量，呈現dose-dependent效應。不同濃度之mitotane可抑制多種steroidogenic enzyme之基因轉錄活性，包含StAR, CYP11A1, CYP11B1, CYP11B2, CYP17 and CYP21，其中HSD3B2未受10 – 40 M mitotane所影響。此外，mitotane對CYP11B1 and CYP11B2 mRNA表現有biphasic effect。在基礎/cAMP路徑活化培養下，mitotane顯著促進ERK磷酸化，SF-1與DAX-1之蛋白質表現並未改變。根據以上實驗結果說明，在基礎與cAMP活化環境下，mitotane非專一性干擾酵素之mRNA表現，進而發揮anti-steroidogenesis作用，其中可能透過ERK相關路徑改變SF-1與DAX-1之蛋白質交互作用。
VEGF對於血管新生與腫瘤生長扮演一重要之角色，同時過去文獻指出ACC腫瘤表現有VEGF接受器。在基礎培養環境，隨著mitotane濃度增加逐漸抑制NCI-H295細胞釋放VEGF；其中40 – 80 M同步降低細胞存活與VEGF釋放量，100 M mitotane對VEGF釋放之抑制效應遠大於對細胞存活。此外，以CoCl2引發之化學性低氧所誘發之VEGF釋放，亦受60 – 100 M mitotane所抑制。依據以上實驗證實，mitotane可能透過改變干擾基礎/低氧所誘發VEGF釋放，進而干擾VEGF-VEGF接受器之autocrine loop，以及引發細胞死亡以發揮anti-tumorigenesis作用。

Adrenocortical carcinoma (ACC) is an extremely rare and aggressive endocrine neoplasm with poor prognosis. Hypercortisolism (Cushing’s syndrome) is the most common complication of functional ACCs. Mitotane not only moderates the signs and symptoms caused by glucocorticoid excess but also improves the metastasis and recurrence of ACC. However, the biological mechanism of anti-steroidogenesis and anti-tumorogenesis of mitotane remains unknown. In this study, adrenocortical carcinoma NCI-H295 cells were used and treated with mitotane (0 - 40 M) for 24 hrs. Mitotane significantly inhibited basal, ACTH (1, 100 nM)-, FK (1, 10 M)- and 8-Br-cAMP (10, 100 M)-induced cortisol secretion in a dose-dependent manner but did not cause cell death. Gene transcription activity of various steroidogenic enzymes including StAR, CYP11A1, CYP11B1, CYP11B2, CYP17 and CYP21 were also diminished by mitotane treatment but not HSD3B2. Interestingly, mitotane expressed biphasic effect on CYP11B1 and CYP11B2 genes. Administration of mitotane potentiated ERK phosphorylation in a dose-dependent manner under both microenvironments. The total protein of SF-1 and DAX-1 were unchanged. These results suggested that mitotane suppressed cortisol production of NCI-H295 cells via interfering basal and cAMP-mediated gene transcription of steroidogenic enzymes. The ERK-mediated signaling might contribute to this effect through altering the protein-protein interaction between SF-1 and DAX-1.
VEGF plays a crucial role in angiogenesis and tumor cell growth and previous studies demonstrated that ACC tumor expresses VEGF receptor. Mitotane suppressed basal VEGF production of ACC cells in a dose-dependent manner. Mitotane (40 – 80 M) inhibited VEGF production and cell viability, while 100 M mitotane expressed the more potential inhibitory effect on VEGF production than cell viability. Moreover, the VEGF production induced by CoCl2-induced hypoxia was suppressed by 60-70 M mitotane. These results suggested that mitotane inhibited tumorigenesis might be through blocking VEGF/VEGFR autocrine loop and/or inducing cell death in NCI-H295 cells.

英文全名與縮寫對照表..................................... 5
中文摘要................................................ 6
英文摘要................................................ 7
第壹章、緒論.............................................. 8
壹、腎上腺 (Adrenal gland).............................. 8
一、組織學.............................................. 8
二、固醇類激素 (Steroid hormone) 生合成路徑............... 8
三、醣皮質固醇受體 (Glucocorticoid Receptor; GR)........ 10
四、醣皮質固醇調節機制................................... 12
五、醣皮質固醇之生理作用................................. 14
六、醣皮質固醇循環與代謝................................. 16
七、轉錄因子與訊息傳遞路徑............................... 17
貳、腎上腺皮質癌 (Adrenocortical Carcinoma; ACC)........ 20
ㄧ、流行病學 (Epidemiology)............................ 20
二、分期與診斷.......................................... 21
三、腫瘤特性與臨床表徵................................... 21
四、治療............................................... 22
五、Mitotane使用現況.................................... 24
六、復發與轉移.......................................... 26
參、低氧............................................... 27
一、低氧與下視丘-腦下腺-腎上腺軸線 (HPA Axis)............. 27
二、低氧與腫瘤.......................................... 28
肆、低氧相關細胞訊息傳遞................................. 31
一、低氧誘發因子 (Hypoxia Inducible Factor-1; HIF-1).... 31
二、血管內皮生長因子..................................... 32
三、PI3K / Akt 路徑.................................... 35
伍、人類腎上腺皮質癌 (ACC) 細胞株 — NCI-H295細胞株........ 40
一、細胞株起源與建立..................................... 40
二、NCI-H295細胞株特性.................................. 40
三、NCI-H295細胞株研究價值.............................. 41
陸、研究動機........................................... 42
第貳章、材料與方法...................................... 44
壹、人類腎上腺皮質癌NCI-H295細胞株之培養.................. 44
一、細胞來源............................................ 44
二、細胞培養............................................ 44
三、繼代培養............................................ 44
四、細胞計數............................................ 45
五、細胞冷凍保存與解凍活化............................... 45
六、建立氣體與與化學低氧培養環境.......................... 46
七、藥物處理............................................ 46
貳、實驗設計............................................ 46
實驗一、NCI-H295細胞之生長曲線........................... 46
實驗二、Mitotane對細胞生長之抑制曲線...................... 47
實驗三、Anti-steroidogenic effects of mitotane......... 47
(一) 基礎狀態 (basal condition)..................... 47
(二) cAMP活化環境 (cAMP-activating condition)....... 48
(三) Mitotane對於轉錄因子SF-1與DAX-1蛋白質表現之效應... 49
實驗四、Anti-tumorigenesis effects of mitotane......... 49
(一) Mitotane對NCI-H295細胞VEGF基礎釋放之效應......... 49
(二) Mitotane對CoCl2化學性低氧誘發VEGF釋放之效應....... 50
參、實驗步驟............................................ 50
一、 醣皮質固酮激素之放射免疫測定 (Radioimmunoassay; RIA)..50
二、 細胞生長測試..................................... 51
三、 細胞蛋白質萃取與定量.............................. 52
四、 PAGE (polyacrylamide gel electrophoresis) 西方墨點轉漬分析 (Western blot)................................... 52
五、 RNA之萃取與純化.................................. 53
六、 逆轉錄聚合酶鏈式反應與即時聚合連鎖反應 (Real-time RT -PCR).................................................. 54
七、 血管內皮生長因子 (VEGF) 之酵素免疫測定法 (Enzyme-linked Immunosorbent Assay; ELISA)........................... 54
八、 統計分析 (Statistical Analysis)................. 55
第叁章、實驗結果........................................ 56
壹、 基礎實驗........................................ 56
貳、 Anit-steroidogenic effects of mitotane......... 56
一、 基礎狀態 (basal condition)........................ 56
二、cAMP活化環境 (cAMP-activating condition)........... 58
三、Mitotane對轉錄因子SF-1與DAX-1蛋白質表現之效應......... 59
參、 Anit-tumorigenic effects of mitotane.......... 59
一、Mitotane 對NCI-H295細胞VEGF基礎釋放之效應............ 59
二、Mitotane 對CoCl2化學性低氧誘發VEGF釋放之效應.......... 60
第肆章、討論............................................ 61
圖表與說明............................................. 67
參考文獻............................................... 85

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