2015-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/672533摘要：骨肉瘤是骨腫瘤中最常見的原發性惡性腫瘤，因骨肉瘤的復發高及易轉移到其他器官，而使化學 治療或放射性治療的效果都不佳，因此如何治療此癌症為一重要的課題。Amphiregulin (AREG)為EGF (epidermal growth factor) -like ligand家族的一員，且具有多種的生物活性，包括細胞生長，分化，神經 再生及骨形成，另外也發現在大腸癌、肺癌、乳癌、骨癌及胰臟癌的病人中AREG過度表現。但AREG 與骨肉瘤的發生及轉移的情況目前並不清楚。由我們初步的結果可以發現給予AREG會增加骨肉瘤細 胞株的移行及細胞内黏著因子（ICAM-1)的表現，另一方面，我們也發現給予EGFR抑制劑會抑制由 AREG所增加骨肉瘤細胞株的移行。因此本計晝首先將研究是否AREG是經由EGFR而調控骨肉瘤細 胞的移行及細胞内黏著因子（ICAM-1)的表現。接著分析AREG經由那些訊息傳遞路徑參與在癌細胞的移行及ICAM-1的表現當中，應是一個治 療骨肉瘤轉移的新方向。由我們初步的結果也發現AREG會增加phosphoinositide-3-kinase (PI3K)及 Akt的磷酸化，另外一方面我們也發現給予骨肉瘤細胞株NF-kB抑制劑（PDTC及TPCK)可以抑制 由AREG所增加的癌細胞移行能力及ICAM-1的表現。因此，第二年期間將研究是否EGFR, PI3K, Akt 及NF-kB訊息傳遞路徑是否參與在AREG所增加的骨肉瘤細胞移行及ICAM-1的表現當中。第三年的期間，我們將利用表現AREG shRNA的骨肉瘤細胞株U2OS/AREG-shRNA及 MG63/AREG-shRNA，觀察其在動物模式中轉移的情況是否較U2OS/control-shRNA及 MG63/control-shRNA少。這計晝的結果將可以了解AREG是否調控骨肉瘤細胞移行及ICAM-1的表現。 而這些結果將可以幫助了解癌細胞轉移的過程，也可以提供臨床上治療的可能性。<br> Abstract: Osteosarcoma is the most common primary malignancy of bone with a poor response to chemotherapy or radiation treatment, making the management of osteosarcomas a complicated challenge. It is characterized by a high malignant and metastatic potential. Amphiregulin (AREG), from the EGF (epidermal growth factor)-like family, which is involved in cancer cellular activities such as proliferation, motility, migration, adhesion and invasion abilities. Recent investigations indicated that overexpression of AREG is frequently found in many types of cancer, including colon, lung, breast and pancreas cancers. However, the expression of AREG in osteosarcoma has not been fully investigated. Our preliminary data showed that AREG increased the migration and expression of intercellular adhesion molecule-1 (ICAM)-1 in human osteosarcoma cells. In addition, we also found that AREG induced cell migration is mediated via EGFR. Involvement of ICAM-1 by AREG/EGFR interaction in AREG-induced cell migration will be examined in this research plan.The analysis of cell signaling for AREG in osteosarcoma cells is crucial for the development of novel approaches for treatment of cancer metastasis. Our preliminary data also showed that AREG induced phosphatidylinositol 3-kinase (PI3K) and Akt phosphorylation. In addition, AREG-induced migration and ICAM-1 expression was antagonized by NF-kB inhibitors (PDTC and TPCK). Whether EGFR/PI3K/Akt and NF-kB signaling pathways are involved in AREG-mediated migration activity and ICAM-1 expression in human osteosarcoma cells will be examined in this research plan.In the third year, we will compare AREG shRNA-transfected osteosarcoma cells (U2OS/AREG-shRNA and MG63/AREG-shRNA) with control siRNA-transfected osteosarcoma cells (U2OS/control-siRNA and MG63/control-siRNA) in pulmonary metastasis using an animal model. The present study will delineate whether AREG regulates the ICAM-1 expression in tumor cells and in tumor metastasis. These results will help us to understand the complicated processes of tumor metastasis, and be beneficial for the development of effective anti-metastasis drugs.骨肉瘤AREGICAM-1轉移OsteosarcomaAREGmigrationICAM-1