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| 题名: | 低氧壓力促進類胰島素生長因子I訊息及活化多功能性小鼠精原幹細胞癌化之探討 |
| 作者: | 江勗良 |
| 贡献者: | 醫學科學研究所 |
| 日期: | 2010 |
| 上传时间: | 2010-08-31 10:39:41 (UTC+8) |
| 摘要: | 幹細胞是體內一群稀少且具有自我更新及分化能力的細胞，而幹細胞所在的微環境中，環境因子對其細胞分化或自我更新等的細胞命運具有決定性的影響，在腫瘤細胞中被認為存在著一群具有和幹細胞相似的特性並具有高度致腫瘤能力的癌幹細胞，其來源與起因並不清楚但目前認為其中一個途徑是透過微環境的逆境 (niche stress) 對細胞產生的壓力進而導致幹細胞癌化，在腫瘤中最常發生的微環境壓力就是低氧及發炎；然而環境因子對於幹細胞的調控是非常複雜的，透過我們所建立的無血清培養系統 (serum-free co-culture system) 發現了IGF-1/IGF-1R的訊息途徑可以調控精源幹細胞 (GSCs ) 對於幹細胞特性 (stemness) 的表現，在我們所建立的無血清環境中加入niche stress (5 % O2) 的條件發現GSCs會高度表現鹼性磷酸酶、幹細胞特性的基因表現上升 (Oct-4、c-Myc)。而且可以看到其細胞群落的大小也有明顯的增加，細胞增生的速度也因為低氧的刺激而增加。此外，在低氧環境下IGF-1和IGF-1R的表現量也都會增加。添加PPP (IGF-1R的抑制劑) 和 LY294002 (PI3K 的抑制劑) 到 AP+GSCs 培養液中，發現 Oct-4、HIF-1α 和 HIF-2α的蛋白表現量都會有顯著的下降，由這些結果我們推測在低氧環境下 HIFs 和 IGF-1 訊息途徑之間的交互作用可以幫助 GSCs 維持未分化的狀態。當我們 AP+GSC 培養在1 % O2 的環境下時可以看到其細胞遷移能力的上升，將培養在低氧環境的 AP+GSC 打入腎包膜中所形成的腫瘤也可以看到類似於 seminoma 的構造；而這些結果高度暗示著精源幹細胞的增生與癌化有可能是受到 IGF-1 訊息途徑與微環境因子之間的交互作用下所產生的影響。
Recent advances in cancer research suggest that there exist cancer stem cells (CSCs) in tumors. The resources of CSCs are still controversial; but the CSCs were originated from its stem cells have been hypothesized (like glioma CSCs and intestine CSCs). The niche stress such as hypoxia effect may provide external signals in stem cell transformation. However, mechanism in regulation of hypoxia-induced stem cell transformation still remains unclear. Our preliminary observations in human pluripotent testicular tumors (seminomas and embryonal carcinomas) showed a high expression level of hypoxia-inducible protein HIF-1α/HIF-2α as well as IGF protein in tissues. This observation strongly highlights the cross-talking of niche hypoxic stress and IGF-1 signaling in transformation of germline stem cells into pluripotent cancers. To address this point, we have successfully established a serum-free stem-niche cell co-culture system to generate pluripotent germline stem cells from neonatal mouse testis (AP+GSCs), and uncovered the role of IGF-1/IGF-1R signaling in germ cell pluripotency. Interestingly, while comparing with the normoxia (20 % O2), the AP+GSCs cells showed in a dramatically increase of alkaline phosphatase activity (AP), cell proliferation, HIF-1α, HIF-2α, Oct-4 protein expression, and pluripotent gene expression (such as Oct-4, Sox2, Nanog, Klf-4, and c-Myc) under hypoxia condition (5 % O2). Moreover, the IGF-1 and IGF-1R expression were also significantly increased under hypoxia. Further analysis by using PPP (a specific inhibitor of IGF-1R phosphorylation) and/or LY294002 (a specific PI3K inhibitor) treatment dramatically reduced the Oct-4 expression as well as HIF-1/HIF-2?峷rotein of AP+GSCs. These observations suggested the regulation of Oct-4/HIF-2α expression by IGF-1/IGF-1R signaling. In summary, our results demonstrated an up-stream regulation of stemness (Oct-4, Sox2, Nanog, and Klf-4) and tumor factor (c-Myc) by hypoxia which was cross-talking with IGF-1/IGF-1R signaling in stem cell transformation under hypoxia condition. |
| 關聯: | 71頁 |
| 描述: | 目錄 I
致謝 III
摘要 IV
ABSTRACT V
第一章 前言 1
1.1 幹細胞 (STEM CELL) 1
1.1.1 幹細胞的分類 2
1.2 精原幹細胞(GERMLINE STEM CELL, GSCS) 4
1.2.1 原生殖細胞 (primordial germ cells, PGCs) 4
1.2.2 精原母細胞 (gonocytes) 4
1.2.3 未分化精原細胞 (Spermatogonial stem cells, SSCs) 4
1.3 幹細胞與低氧微環境 6
1.4 精原幹細胞的微環境 7
1.4.2 低氧環境下精原幹細胞的基因表現 8
1.5 癌幹細胞(CANCER STEM CELL，CSCS) 2
1.6 氧氣濃度與癌幹細胞的關係 3
1.7 缺氧誘導蛋白 (HYPOXIA INDUCIBLE FACTOR, HIF) 4
1.7.1 HIFs的調控 5
1.8 研究動機 6
第二章 材料與方法 7
2.1 實驗動物 7
2.2 細胞培養 7
2.2.1小鼠睾丸組織精原幹細胞初級培養 (Primary culture) 7
2.2.2 培養小鼠精原幹細胞於低氧環境 (Hypoxia) 9
2.3 鹼性磷酸酶 (ALKALINE PHOSPHATASE, AP) 活性測定 10
2.3.1 以BCIP/ NBT來測定小鼠精原幹細胞的鹼性磷酸酶活性 10
2.3.2 以鹼性磷酸酶試劑組來測定小鼠精原幹細胞的鹼性磷酸酶活性 11
2.4 基因表現測定 12
2.4.1 RNA萃取 12
2.4.2 反轉錄聚合酶連鎖反應 (RT-PCR) 14
2.4.3 洋菜膠體電泳 (Agarose gel electrophoresis) 17
2.5 蛋白質表現測定 18
2.5.1 蛋白質萃取 18
2.5.2 SDS膠體電泳 (SDS-PAGE) 18
2.5.3 西方墨點法 (Western blotting) 20
2.5.4 Slot-blotting 22
2.6 小鼠精原幹細胞訊息傳遞路徑的相關調控 24
2.7 5-BROMODEOXY-URIDINE (BRDU) INCORPORATION 25
2.8 免疫細胞染色 26
2.9 免疫組織染色 (IMMUNOHISTOCHEMISTRY) 28
2.10 細胞遷移分析 30
第三章 實驗結果 32
3.1 胞外基質對精原幹細胞的影響 32
3.2 氧濃度對精原幹細胞生長及代謝的影響 32
3.3 低氧環境下精原幹細胞的基因表現 33
3.4 精原幹細胞在低氧環境下HIFS 與生長因子訊息傳遞與精原幹細胞之交互作用 34
3.5 低氧環境下對於精原幹細胞增生的影響 35
3.6 精原幹細胞在低氧環境下的遷移作用 35
3.7 低氧環境下對精原幹細胞的癌化作用 36
第四章 討論 37
4.1 無血清共同培養系統與精原幹細胞的關係 37
4.2 低氧環境下對精原幹細胞的影響 38
4.3 低氧環境與精原幹細胞的遷移作用 39
4.4 低氧環境與生長因子之間的交互作用 40
第五章 圖表 41
FIG.1 胞外基質 (ECM) 對於精原幹細胞生長與鹼性磷酸酶的影響 42
FIG. 2 氧濃度對精原幹細胞鹼性磷酸酶活性的影響 44
FIG. 3 氧濃度對精原幹細胞能量代謝的影響 46
FIG. 4 低氧環境下對精原幹細胞的影響 48
FIG.5 精原幹細胞在低氧環境下HIFS 與生長因子訊息傳遞與精原幹細胞之交互作用 50
FIG. 6 低氧環境下對於精原幹細胞細胞週期的影響 52
FIG. 7 精原幹細胞在低氧環境下的遷移作用 54
FIG. 8 低氧環境下對精原幹細胞的癌化作用 56
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