Chondrosarcoma (軟骨肉瘤) 是骨骼系統中發生率為第二高的腫瘤，在臨床上以化學治療或放射線 治療的效果都不佳，因此如何治療此癌症為一重要的課題。CCN4 為CCN (Cyr61, CTGF, Nov)家族的 一員。在之前的研究報告中發現癌症病人中其CCN4 過度表現。但是，CCN4 與軟骨肉瘤的發生及轉 移的情況目前並不清楚。由我們初步的結果發現外給CCN4 會增加軟骨肉瘤細胞株的移行。另外一方 面，我們也發現CCN4 會增加MMP-2 表現。因此本計畫首先將研究是否CCN4 可調控軟骨肉瘤細胞 的移行及MMP-2 的表現。 分析CCN4 經由那些訊息傳遞路徑參與在移行及MMP-2 的表現當中，應是一個治療軟骨肉瘤 轉移的新方向。由我們初步的結果也發現CCN4 會增加focal adhesion kinase (FAK) 及ERK 的磷酸 化，另外一方面我們也發現給予軟骨肉瘤細胞株NF-B inhibitors (PDTC and TPCK) 可以抑制由 CCN4 所增加的癌細胞移行能力及MMP-2 的表現。因此，第二年期間將研究是否FAK, ERK 及 NF-B 訊息傳遞路徑是否參與在CCN4 所增加癌細胞移行及MMP-2 表現當中。 在第三年的期間，我們將利用表現CCN4 shRNA 的軟骨細胞株JJ012/CCN4-shRNA，觀察其在動 物模式中轉移的情況是否較JJ012/control-shRNA 少。這計畫的結果將可以了解CCN4 是否調控軟骨肉 瘤細胞移行及MMP-2 的表現。而這些結果將可以幫助我們了解癌細胞轉移的過程也可以提供臨床上 治療的可能性。 Chondrosarcoma is the second most common malignancy of bone with a poor response to currently-used chemotherapy or radiation treatment, making the management of chondrosarcomas a complicated challenge. CCN4 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matricellular proteins. Recent investigations indicated that overexpression of CCN4 is frequently found in many types of cancer. However, the expression of CCN4 in chondrosarcomas has not been fully investigated. Our preliminary data showed that CCN4 increased cell migration in human chondrosarcoma cells. In addition, we also found that CCN4 increased MMP-2 expression. Involvement of MMP-2 up-regulation in CCN4-induced cell migration will be examined in this research plan. The analysis of cell signaling for CCN4 in chondrosarcoma cells is crucial for the development of novel approaches for treatment of cancer metastasis. Our preliminary data also showed that CCN4 induced focal adhesion kinas (FAK) and ERK phosphorylation. In addition, CCN4-induced migration and MMP-2 expression was antagonized by NF-κBinhibitors (PDTC and TPCK). Whether FAK/ERK and NF-κB signaling pathways are involved in CCN4-mediated migration activity and MMP-2 expression in human chondrosarcoma cells will be examined in this research plan. In the third year, we will compare CCN4 shRNA-transfected chondrosarcoma cells (JJ012/ CCN4-shRNA) with control shRNA-transfected chondrosarcoma cells (JJ012/control-shRNA) in pulmonary metastasis using an animal model. The present study will delineate whether CCN4 regulates the MMP-2 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.
