2016-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658007摘要：Osteosarcoma (骨肉瘤）是骨胳系統中發生率為第一高的腫瘤，在臨床上以化 學治療的效果仍無法完全治癒，放射線治療效果很差，因此如何治療此癌症為一 重要的課題。CXCL1 (GRO- a)為Chemokine家族的一員，在過去文獻發現， CXCL1可以使單核球細胞的活化及黏著。在之前的研究報告中發現在大腸癌、肺 癌、乳癌及胰臟炎的病人中CXCL1有過度表現。但CXCL1與骨肉瘤細胞株的移行 及細胞的CXCR2的表現並不明朗。本子計晝將研究是否CXCL1會促進骨肉瘤細胞 分泌VCAM-1，進而促進骨肉瘤細胞轉移。而由我們初步的結果發現CXCL1會增 加骨肉瘤細胞分泌VCAM-1的表現，另外給予CXCR2抑制劑則可以抑制由CXCL1 所增加VCAM-1的表現。因此，本計晝將研究CXCL1所增加VCAM-1的表現是否 有CXCL1 /CXCR2的交互作用參與。分析CXCL1/CXCR2經由那些訊息傳遞路徑參與在VCAM-1的表現當中，應 可以了解癌細胞轉移的過程也可以提供臨床上治療的可能性。由我們初步的結果 也發現CXCL1 會增加FAK, 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FAK, PI3K, Akt及NF-kB抑制劑可以抑制由 CXCL1所增加的VCAM-1的表現。因此，第二年期間將研究CXCL1所增加 VCAM-1的表現，FAK, PI3K, Akt及NF-kB訊息傳遞路徑是否參與其中。第三年的期間，我們將利用表現CXCL1 shRNA的骨肉瘤細胞株 U2OS/CXCL1-shRNA及MG63/CXCL1-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 CXCL1是否調控骨肉瘤細胞移行及VCAM-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 fair response to chemotherapy and poor response to radiation treatment, making the management of osteosarcomas a complicated challenge. It is characterized by a high malignant and metastatic potential. CXCL1 (GRO-a), from the chemokines family, which is involved in cancer cellular activities such as proliferation, cell motility, migration, adhesion and invasion abilities. It has been reported that the effect of CXCL1 is mediated via CXCR2. However, the effects of CXCL1 on human osteosarcoma cells are largely unknown. Our preliminary data showed that CXCL1 increased the migration and expression of vascular cell adhesion molecule-1 (VCAM)-1 in human osteosarcoma cells. In addition, we also found that CXCL1 induced cell migration is mediated via CXCR2. Involvement of VCAM-1 by CXCL1/CXCR2 interaction in CXCL1-induced cell migration will be examined in this research plan.The analysis of cell signaling for CXCL1 in osteosarcoma cells is crucial for the development of novel approaches for treatment of cancer metastasis. Our preliminarydata also showed that CXCL1 induced FAK, phosphatidylinositol 3-kinase (PI3K) and Akt phosphorylation. In addition, CXCL1-induced migration and VCAM-1 expression was antagonized by NF-kB inhibitors (PDTC and TPCK). Whether CXCR2/PI3K/Akt and NF-kB signaling pathways are involved in CXCL1-mediated migration activity and VCAM-1 expression in human osteosarcoma cells will be examined in this research plan.In the third year, we will compare CXCL1 shRNA-transfected osteosarcoma cells (U2OS/CXCL1-shRNA and MG63/CXCL1-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 CXCL1 regulates the VCAM-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.