AEG-1/LYRIC 於頭頸部鱗狀細胞癌中生物功能之研究

Abstract

背景：雖然近年來癌症治療方式有長足進步，晚期頭頸部鱗狀細胞癌之存活率依舊不佳。近年研究顯示，astrocyte elevated gene-1 (AEG-1)此一單次穿膜蛋白雖無任何已知之功能區段，但仍在多種人類癌症中高度表現並與轉移發生及較差之存活率相關。 結果：頭頸部鱗狀細胞癌中AEG-1之高度表現與區域淋巴結轉移及較差之五年存活率呈正相關。將頭頸部鱗狀細胞癌細胞株中之AEG-1敲減表現後，其細胞群落形成、移動、及入侵能力皆為下降。此外，AEG-1敲減表現後之頭頸部鱗狀細胞癌細胞株轉植於免疫不全小鼠中所形成的腫瘤體積及肺部轉移病灶亦皆減少。我們並發現AEG-1可上升NF-κB中p65次單元之磷酸化，進而調控頭頸部鱗狀細胞癌細胞表現MMP1酵素。同時頭頸部鱗狀細胞癌之臨床檢體AEG-1、磷酸化p65及MMP1之表現互相呈現統計上有意義之相關性。 結論： AEG-1於頭頸部鱗狀細胞癌中高度表現與淋巴結轉移相關，並為頭頸部鱗狀細胞癌臨床預後之負向指標。

Background: The survival rate of head and neck squamous cell carcinoma (HNSCC) at advanced stage is poor, despite contemporary advances in treatment modalities. Recent studies have indicated that astrocyte elevated gene-1 (AEG-1), a single transmembrane protein without any known functional domains, is overexpressed in various malignancies and is implicated in both distant metastasis and poor survival. Results: High expression of AEG-1 in HNSCC was positively correlated with regional lymph node metastasis and a poor 5-year survival rate. Knockdown of AEG-1 in HNSCC cell lines reduced their capacity for colony formation, migration and invasion. Furthermore, decreased tumor volume and metastatic foci were observed after knockdown of AEG-1 in subcutaneous xenografts and pulmonary metastasis assays in vivo, respectively. We also demonstrated that AEG-1 increased phosphorylation of the p65 subunit of NF-κB, and regulated the expression of MMP1 in HNSCC cells. Moreover, compromised phosphorylation of the p65 (RelA) subunit of NF-κB at serine 536 was observed upon silencing of AEG-1 in HNSCC cell lines and the expression status of AEG-1, phosphorylated p65 and MMP1 are mutually correlated in clinical specimens. Conclusion: High expression of AEG-1 is associated with lymph node metastasis and is a negative prognostic parameter for clinical outcome in HNSCC. Keywords: Astrocyte elevated gene-1 (AEG-1), head and neck squamous cell carcinoma (HNSCC), metastasis, matrix metalloproteinase 1 (MMP1), p65