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研究生： 鄒宇涵
Yu-Han Tsou
論文名稱： 第二型內皮素與第一型類胰島素生長因子對3T3-L1前脂肪細胞生長刺激作用的信息傳導路徑
Signal transduction pathway of endothelin-2 with IGF-I in the growth stimulation of 3T3-L1 preadipocytes
指導教授： 高永旭
Yung-Hsi Kao
口試委員:
學位類別： 碩士
Master
系所名稱： 生醫理工學院 - 生命科學系
Department of Life Science
論文出版年： 2021
畢業學年度： 109
語文別： 中文
論文頁數： 75
中文關鍵詞： 第二型內皮素 、第一型類胰島素生長因子 、前脂肪細胞
外文關鍵詞： endothelin-2, IGF-I, preadipocyte
相關次數： 點閱：12  下載：0 
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    • 內皮素（ETs）是一種21個氨基酸的肽激素，從豬主動脈內皮細胞培養上清液中分離出來，被稱為有效的血管收縮劑和加壓劑。儘管有文獻指出ETs增強第一型類胰島素生長因子（IGF-I）對前列腺癌細胞生長的刺激作用，但尚未發現ET-2是否與IGF-I有相互作用在脂肪細胞的報導。使用3T3-L1前脂肪細胞，我們發現單獨的ET-2對細胞生長沒有影響，如在細胞數量，細胞存活和BrdU incorporation的變化所表明。在存在IGF-1的情況下，ET-2增強了IGF-1誘導的細胞數量和細胞增殖的增加。當檢驗ET-2信號通路時，透過內皮素受體的特異性抑製劑ETAR拮抗劑（BQ610）而不是ETBR拮抗劑（BQ788）的預處理阻止了ET-2對IGF-I誘導的細胞數量和細胞存活增加的增強作用。進一步的在Western blot中表明，ET-2、IGF-I及其組合傾向於時間依賴性的刺激AKT、ERK和STAT3蛋白的磷酸化。有趣的是，與單獨的IGF-I相比，ET-2在一小時增強了IGF-I刺激的STAT3磷酸化蛋白，但未增強AKT或ERK1/2。但是，在15和30分鐘時預處理ET-2可以增強IGF-I刺激的AKT和ERK蛋白的磷酸化。此外，預處理STAT3抑制劑（AG490）、ERK1/2抑制劑（U0126）和PI3K/AKT抑制劑（Wortmannin）阻止了ET-2和IGF-I對細胞數和細胞存活的刺激，同時也分別降低各自pSTAT3，pAKT和pERK蛋白水平。總之，STAT3以及較小程度的AKT和ERK蛋白對於ET-2和IGF-I以ETAR依賴性而不是ETBR依賴性的方式對前脂肪細胞的生長產生協同作用是必需的。

    Endothelins (ETs) are a 21 amino acid (aa) peptide hormone that was known as a potent vasoconstrictor and pressor substance isolated from the culture supernatant of porcine aortic endothelial cells. Although the ETs have been also reported to potentiate the stimulatory effect of insulin-like growth factor (IGF)-I on the growth of prostate cancer cells, no reports are found whether ET-2 interacts with IGF-I in fat cells. Using 3T3-L1 preadipocytes, we found that ET-2 alone had no effect on cell growth, as indicated by changes in levels of cell number, BrdU incorporation, and cell viability. In the presence of IGF-I, ET-2 enhanced IGF-I-induced increases in both cell number and cell proliferation. When the ET-2 signaling pathway was examined, pretreatment with the specific inhibitors of endothelin receptors, ETAR antagonist (BQ610) but not ETBR antagonist (BQ788), prevented the enhancing effect of ET-2 on IGF-I-induced increases in both cell number and cell viability. Further Western blotting analysis showed that ET-2, IGF-I, and their combination tended to time-dependently stimulate phosphorylations of AKT, ERK, and STAT3 proteins. Interestingly, ET-2 at 1 h enhanced IGF-I-stimulated phosphorylation of STAT3, but not AKT or ERK1/2, proteins when compared to IGF-I alone. But, pretreatment with ET-2 at 15 and 30 min enhanced IGF-I-stimulated phosphorylation of AKT and ERK proteins. Moreover, pre-treatment with STAT3 inhibitor (AG490), ERK1/2 inhibitor (U0126), and PI3K/AKT inhibitor (wortmannin) prevented the stimulation of ET-2 and IGF-I in cell number and cell viability, respectively, as well as reducing the level of respective pSTAT3, pAKT, and pERK proteins. In conclusions, STAT3 and, to a lesser extent of AKT and ERK proteins are necessary for the synergistic effect of ET-2 and IGF-I on the growth of preadipocytes in an ETAR-dependent and ETBR-independent manner.

    摘要 I ABSTRACT II 致謝 III 目錄 IV 表目錄 VII 圖目錄 VIII 縮寫與全名對照表 IX 壹、 前言 1 1-1 肥胖症與脂肪細胞 1 1-2 內皮素 2 1-2-1 第一型和第三型內皮素的差異 2 1-2-2第二型內皮素 3 1-2-3 Endothelin之訊息傳導路徑 3 1-2-4 ET-2與脂肪細胞的關係及其訊息傳導 4 1-3 第一型類胰島素生長因子 5 1-3-1 IGF-I之特性 5 1-3-2 IGF-I之訊息傳導路徑 5 1-3-3 IGF-I與脂肪細胞之關係及訊息傳導 6 1-4 研究動機與目的 6 貳、 材料與方法 7 2-1 實驗材料 7 2-2 實驗方法 7 2-2-1 細胞培養 7 2-2-2 ET-2、IGF-I和抑制劑處理 7 2-2-3 細胞生長實驗 7 2-2-3-1 細胞計數 7 2-2-3-2 細胞存活率試驗（MTT assay） 8 2-2-3-3 細胞增殖分析（BrdU incorporation） 8 2-2-4 蛋白質萃取與定量 9 2-2-5 西方墨點法 9 2-3 統計分析 11 參、 結果 12 3-1 ET-2和IGF-I對3T3-L1生長的影響 12 3-2 ET-2對IGF-I 之強化作用是透過ETAR不是ETBR而影響細胞的生長 12 3-3 ET-2對IGF-I之強化作用是透過 STAT3蛋白而影響3T3-L1細胞生長 13 3-4 ET-2和IGF-I可能透過PI3K/AKT蛋白而影響細胞生長 14 3-5 ET-2和IGF-I可能透過MAPK家族蛋白影響細胞生長 15 3-6 STAT3，AKT和EKR1/2蛋白之間的交互作用（CROSS TALK） 16 肆、 討論 18 伍、 結論 22 陸、 參考文獻 23 表1、材料名稱、產品型號及採購來源 34 表 2、抗體來源與稀釋比例 36 圖 一、ET-2和IGF-I的協同作用增加了3T3-L1前脂肪細胞中的（A）細胞數、（B）細胞增殖和（C）細胞增殖存活率。 37 圖 二、ET-2和IGF-I的協同作用是通過ETAR路徑增加前脂肪細胞的生長，但不通過ETBR。 40 圖 三、JAK2/STAT3抑製劑（AG490）抑制ET-2對IGF-I刺激3T3-L1生長之強化作用 42 圖 四、PI3K/AKT抑製劑（Wortmannin）抑制ET-2對IGF-I刺激前脂肪細胞生長之強化作用。 44 圖 五、ERK1/2抑製劑（U0126）抑制ET-2和IGF-I刺激前脂肪細胞生長之協同作用。 46 圖 六、透過STAT3拮抗劑（AG490）、PI3K/AKT拮抗劑（Wortmannin）以及ERK1/2拮抗劑（U0126）觀察各蛋白之間的交互作用。 48 圖 七、內皮素-2對3T3-L1前脂肪細胞生長之機制。 49 圖 八、IGF-I對3T3-L1前脂肪細胞生長之機制。 50 圖 九、ET-2和IGF-I之協同作用對3T3-L1前脂肪細胞生長之機制。 51 柒、 附錄 52 附錄一、ET-2, IGF-I和抑制劑配製方法與濃度 52 附錄二、Lysis buffer preparation (1mL) 53 附錄三、使用試劑之配方 54 附錄四、JNK，cJun，p38之time course。 57 附錄五、不同血清條件下對ET-2和IGF-I之協同作用之影響 58 附錄六、無血清條件下，處理藥物1小時之蛋白質的表現。 59 附錄七、實驗中每種抗體的完整印跡圖。 61

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