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National Chung Hsing University Institutional Repository - NCHUIR > 生命科學院 > 生物化學研究所 > 依資料類型分類 > 碩博士論文 >  蛇床子素抑制第一型類胰島素生長因子誘發人類腦癌細胞上皮及間質細胞轉換之研究

Please use this identifier to cite or link to this item: http://nchuir.lib.nchu.edu.tw/handle/309270000/152340

標題: 蛇床子素抑制第一型類胰島素生長因子誘發人類腦癌細胞上皮及間質細胞轉換之研究
Osthole Inhibits Insulin-Like Growth Factor-I-Induced Epithelial-Mesenchymal Transition in Human Brain Cancer Cells
作者: 林家慶
Lin, Jia-Ching
Contributors: 高振益
Jung-Yie Kao
生物化學研究所
關鍵字: 蛇床子素;第一型類胰島素生長因子;上皮及間質細胞轉換;腦癌
Osthole;Insulin-Like Growth Factor-I;Epithelial-Mesenchymal Transition;Human Brain Cancer
日期: 2013
Issue Date: 2013-11-07 13:21:31 (UTC+8)
Publisher: 生物化學研究所
摘要: 惡性神經膠質瘤是一種致死率高的癌症。研究指出,癌細胞高度的轉移侵襲特性是腦癌病患的死亡的主因。上皮及間質細胞轉換(Epithelial-Mesenchymal Transition, EMT)過程可被許多不同的生長因子所誘發,也是癌細胞發生轉移的最關鍵起始步驟。蛇床子素(Osthole)為傳統消炎用中草藥,目前已知Osthole具有抑制表皮肝細胞生長因子(HGF)誘發乳癌EMT的能力,然而,關於Osthole抑制腦癌的相關研究卻相當稀少。
本研究以IGF-1處理人類腦癌細胞株GBM8401後,細胞型態與間距會變細長而分散,ZO-1表現量會下降,Vimentin表現量則會上升,證實IGF-1可以誘發腦癌細胞EMT。而當以Osthole處理GBM8401細胞後,Osthole反而能抑制IGF-I所引起的型態改變,同時回復ZO-1的表現並抑制Vimentin。免疫染色的結果也顯示,經Osthole處理後Vimentin表現量會下降。以相同條件進行傷口癒合試驗也可觀察到Osthole能抑制IGF-I引起的細胞爬行能力。綜合以上實驗結果,Osthole能夠抑制IGF-I在腦癌中誘導的EMT。進一步以雙重冷光酵素報導試驗與及時聚合酶鏈鎖反應結果得知,Osthole抑制IGF-I所引起的EMT現象主要是抑制在基因轉錄層面。深入探討Osthole對IGF-I下游訊息路徑影響,發現Osthole能夠降低IGF-1下游Akt和GSK3β蛋白磷酸化的情形,恢復GSK3β抑制EMT轉錄因子Snail、Twist表達的生物活性,進而抑制Snail、Twist等轉錄因子抑制EMT的發生。由此可推論Osthole能夠藉由阻斷PI3K-Akt路徑的進行來抑制EMT的發生。希望未來Osthole能運用到癌症醫療上,為腦癌治療提供新的藥物。
Malignant glioma is one of the most lethal types of tumor in human. It has been shown that the highly metastasis and invasion result in death of the brain cancer patients. The EMT is the crucial step for cancer cells to initiate the metastasis which could be induced by many growth factors. Previous studies showed that the Type-I-Insulin-like growth factor (IGF-1) could induce the mammary epithelial cells and prostate cancer cells EMT through the (PI3-kinase)-Akt pathway and mitogen-activated protein (MAP) kinase pathways. Osthole is the Chinese Traditonal drug for anti-inflammatory. Previous study showed that Osthole could inhibit the HGF-induced epithelial-mesenchymal transition in breast cancer cells. However, it is still unclear whether Osthole could inhibit human brain cancer.
In this study, we found that human brain cancer GBM8401 cells were converted to fibroblastic phenotype and the space between the cells became expanded in response to IGF-I treatment. Epithelial marker, ZO-1 was down-regulated and mesenchymal marker vimentin was up-regulated simultaneously. Our results illustrated that IGF-I was able to induce EMT in human brain cancer cells, and Osthole would reverse IGF-I-induced morphological changes, up-regulated the expression of ZO-1 and down-regulated the expression of and vimentin. Immunofluorescent staining also demonstrated that vimentin was down-regulated by Osthole pretreatment. Moreover, wound-healing assay also showed that Osthole can inhibit IGF-I-induced migration of human brain cancer cells. By using dual-luciferase reporter assay and Real-time PCR, we demonstrated that Osthole inhibited IGF-I-induced EMT at the transcriptional level. We further investigated the effect of Osthole on IGF-I signaling pathway. We found that Osthole decreased the phosphorylation of Akt and GSK3β, recovered the GSK3β bioactivity in inhibiting EMT transcription factor Snail, twist expression. These results showed that Osthole inhibited IGF-I-induced EMT by blocking (PI3-kinase)-Akt pathway. We hope that Osthole can be used in anticancer therapy and be a new therapeutic medicine for brain cancer in the future.
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