臺灣博碩士論文加值系統

多環芳香烴受體 (Aryl hydrocarbon receptor, AhR) 為一配體活化之轉錄因子，當接觸到環境汙染物多環芳香烴 (polycyclic aromatic hydrocarbon, PAH) 時AhR會被活化並啟動下游基因轉錄。其中苯芘(benzo[a]pyrene, B[a]P)屬多環芳香烴家族之一，暴露來源多為環境中燃燒不完全所產生之廢氣，諸如：汽機車廢氣、森林燃燒、香菸與烹飪油煙等。過去文獻指出苯芘可能與人體肺癌發生有關，並造成多種腫瘤惡化，其主要機轉被認為透過活化AhR所調控。腫瘤發展過程中，細胞失去上皮細胞緊密結合型態，轉變為間質細胞型態之過程稱為細胞上皮-間質轉換 (epithelial - mesenchymal transition, EMT)，EMT不僅促進胚胎發育過程中型態改變，在癌症中更促使癌細胞侵襲及轉移。近年許多文獻指向AhR於EMT中扮演重要角色，其中TCDD活化AhR可誘導乳癌細胞諸多EMT指標蛋白改變。此外，亦有文獻報導AhR與調控細胞骨架重組及細胞型態有關。然而，對於AhR如何調控EMT目前仍屬未知。細胞自噬為一種細胞自我保護機制，於腫瘤惡化過程中扮演重要角色，主要因其調控了細胞週期與死亡，對於EMT發生具有雙面刃式的調控作用。有證據指向暴露PAHs所導致的腫瘤惡化會伴隨自噬的發生，然而PAHs引發細胞自噬是否與AhR訊息傳遞有關仍不清楚，由於AhR可能於EMT扮演重要角色，因此本研究主要目的在於了解AhR調控EMT的過程是否與細胞自噬有關。首先我們發現不同肺癌細胞A549、H1299與CL1-5中AhR蛋白表現量愈高其細胞侵襲能力較弱，而AhR蛋白表現少則會增加細胞侵襲能力。此外，免疫螢光染色結果也顯示，透過改變AhR蛋白表現量，可以調控LC3I-LC3II蛋白轉換趨勢，我們也發現AhR表現量少之CL1-5與H1299其細胞自噬能力較A549大， A549及CL1-5之細胞型態與細胞侵襲能力也可因改變AhR蛋白表現而改變。接著我們以A549 AhR靜默之細胞模式，證明了AhR靜默可透過改變BNIP3 ubiqutination之降解途徑以促發細胞自噬。另一方面，苯芘可誘發肺癌細胞之移行能力，並且比較A549、H1299及CL1-5之細胞移行能力，可以發現AhR表現量較少之H1299與CL1-5對苯芘誘導之細胞移行能力大於A549細胞。其中，苯芘亦改變三株細胞之EMT相關標記、減少BNIP3之蛋白表現並促使細胞自噬。進一步分析苯芘誘發ROS與調控細胞骨架蛋白Rac1/cdc42與FAK間之關聯，亦可發現抑制細胞自噬可回復苯芘誘發之ROS與Rac1/cdc42表現量增加之現象。綜合以上，此研究觀察到內生性AhR蛋白表現量是調控細胞自噬的重要角色之一，並解釋AhR透過BNIP3調控細胞自噬，進而改變EMT相關指標蛋白，導致癌細胞遷移及侵襲能力受到影響。

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which could be activated to switch on target gene transcription by polycyclic aromatic hydrocarbon (PAHs) exposure. One of the PAHs family, benzo[a]pyrene (B[a]P), source of exposure include traffic exhaust, forest fires, cigarette smoking, and cooking Oil. Such of studies indicate that B[a]P exposure might related to lung tumorigenesis and caused several tumor progression by altering AhR regulation. When the tumor progression, epithelial cells lose its intercellular adhesion during critical phases is a process called epithelial - mesenchymal transition (EMT), which not only regulate embryonic development but promote cancer invasion and metastasis. Previous studies have revealed that AhR play an critical role on EMT, which indicated TCDD-activated AhR induced EMT marker changed in breast cancer cell. In addition, AhR have been shown that involved in cytoskeleton and cell morphology regulation. However, the detailed mechanism of AhR-regulated EMT is still unknown. Autophagy represents a protective function and have a role on tumor progression because of its function on cell cycle and cell death, it regulated EMT in biphasic manners. Some studies have shown the tumor progression induced by PAH were accompany with autophagy, but there were unclear mechanism between PAHs-induced autophagy and AhR signaling. Although AhR could influence EMT progression, in this study, we research the AhR-regulated EMT and autophagy cross-talk signaling. We have found that the level of AhR expression in different lung cancer cells, A549, H1299, and CL1-5 were correlated with their invasive potential. AhR in higher basal level, showed a lower invasive ability, in contrast, AhR in lower level with a higher invasive potential. Moreover, the immunostaining have shown LC3I-LC3II transition were changed by AhR protein expression. We also found the CL1-5 and H1299 cells with lower AhR level revealed higher autophagy than A549 cells. The cell invasive potential and morphology were also changed by altering AhR protein expression. Yet, the AhR silenced in A549 cell confirmed BNIP3 ubiquitination were reduced and instead of on autophagy-lysosome degradation pathway. This result indicated AhR could promote BNIP3 ubiquitination for proteasome degradation. On the other hand, B[a]P- induced different invasive potential in three lung cancer cells. H1299 and CL1-5 with higher invasive potential then A549 cells. B[a]P also influenced EMT marker expression , decreased BNIP3 protein expression and enhanced autophagy in three lung cancer cells. Further, the relation between ROS induced by B[a]P and Rac1/cdc42, FAK were also comfirmed. We found autophagy inhibition reversed B[a]P-induced ROS and Rac1/cdc42 protein expression. Taken together, we found the a cross-linking between AhR signaling and autophagy by endogenous AhR regulation, which regulated autophagy to alter EMT marker through interacting with BNIP3 and lead the cancer cell migration changed.

縮寫表（Abbreviations）..................................III
中文摘要.................................................IV
Abstract.................................................VI
第一章 緒論 ( Introduction ).............................2
1.1多環芳香烴受體（Aryl hydrocarbon receptor; AhR）.......2
1.2上皮間質轉移 (Epithelial-Mesenchymal Transition, EMT)作用........................................................6
1.3 AhR對EMT之影響........................................8
1.4細胞自噬(Autophagy)....................................9
1.4.1 Macroautophagy:.....................................12
1.4.2 Microautophagy:.....................................13
1.4.3 Chaperone-mediated autophagy (CMA):.................14
1.5細胞自噬對細胞EMT之影響................................15
1.6研究動機...............................................16
第二章 材料與方法 (Materials and methods).................20
2.1 實驗材料.............................................20
2.1.1細胞株 (Cell lines)..................................20
2.1.2藥品與試劑 (Chemicals and Reagents)..................20
2.1.3抗體 (Antibodies)....................................22
2.1.4質體 (Plasmids)......................................22
2.2 實驗方法.............................................22
2.2.1細胞培養 (Cell culture)..............................22
2.2.2細胞總蛋白質液收集 (Cell lysate collection)..........23
2.2.3西方墨點法 (Western blot)............................23
2.2.4免疫沉澱法 (Immunoprecipitation).....................24
2.2.5細胞RNA萃取 (RNA extraction).........................24
2.2.6反轉錄聚合酶鏈鎖反應 (Reverse Transcription Polymerase Chain Reaction, RT-PCR)...................................24
2.2.7免疫螢光染色 (Immunofluorescence)....................25
2.2.8細胞爬行與侵襲試驗 (Cell migration/invasion assay)...26
2.2.9單丹(磺)酰戊二胺染色 (MDC staining)..................26
2.2.10細胞內reactive oxygen species (ROS)測定.............27
2.2.11穿透式電子顯微鏡 (Transmission electron microscopy, TEM)......................................................27
2.2.12小鼠肺部轉移試驗 (Pulmonary metastasis assay).......27
2.2.13免疫組織染色........................................28
2.2.14統計分析 (Statistic analysis).......................28
第三章 AhR調控細胞自噬活化並抑制肺癌細胞的爬行............29
第四章 苯芘活化AhR對調控細胞自噬機制之探討................66
第五章 結論 (Conclusion).................................87
參考文獻..................................................90
著作......................................................108

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