Lipocalin-2與缺氧相關因子的調控及其在口腔癌致癌過程的表現

Lipocalin-2(LCN2)是Lipocalin蛋白家族的一分子。LCN2可與基質金屬蛋白水解酶(Matrix metalloproteinase-9；MMP-9)結合而促進MMP-9的活性，並且使得MMP-9不被降解。 LCN2除了在人類各種發炎反應會上升，近年來也發現其與腫瘤生成有關。但是LCN2與口腔癌的相關性仍不清楚。因此，我們利用酵素聯結免疫吸附法觀察了口腔鱗狀細胞癌(oral squamous cell carcinoma; OSCC)病人與健康對照組血漿中LCN2、MMP-9與LCN2/MMP-9複合物的表現。結果顯示OSCC病人血漿中LCN2、MMP-9與LCN2/MMP-9複合物的濃度明顯高於健康對照組。並且LCN2的表現量與腫瘤大小、TNM分期有關，但與淋巴轉移、遠端轉移無關。而我們也進一步發現病人血漿中LCN2、MMP-9與LCN2/MMP-9複合物這三個指標彼此之間皆呈現正相關。我們進一步想釐清LCN2在口腔癌細胞株中的分子機轉。在篩選了穩定表達LCN2的SCC9口腔癌細胞株發現其細胞移動能力降低，也發現到缺氧相關因子，包括缺氧誘導因子1α (Hypoxia-inducible factor 1 alpha；HIF-1α) 與碳酸酐酶IX (carbonic anhydrase IX; CAIX)，無論是在mRNA與蛋白表現皆下降，且細胞的移動能力降低是受到CAIX的影響。因此我們推測在OSCC病人血漿中LCN2的表現可以當作一項非侵入性指標來預測OSCC病人的病程，並且LCN2在口腔癌細胞株中是透過調控缺氧相關因子的表現量使得細胞移動能力降低。

Lipocalin 2 (LCN2) is one member of a larger protein family known as lipocalins. Recent evidence demonstrated that LCN2 is induced in many types of human cancer, while detection of its complex with matrix metalloproteinase (MMP)-9 is correlated with the cancer-disease status. This study attempted to evaluate plasma levels of LCN2, MMP-9, and their complex (LCN2/MMP-9) during the diagnostic work-up of patients with oral squamous cell carcinoma (OSCC) and investigated their correlations with disease progression. Significantly higher levels of LCN2, MMP-9, and LCN2/MMP-9 were detected in 195 patients with OSCC, as compared to 81 healthy controls. Furthermore, plasma levels of LCN2, MMP-9, and LCN2/MMP-9 in OSCC patients were significantly correlated with each other and were associated with more-advanced clinical stages and/or a larger tumor size, but were not associated with positive lymph node metastasis or distal metastasis. The potential underlying molecular mechanism for the involvement of LCN2 in oral cancer cell lines was also investigated to show that a stable overexpression of LCN2 in SCC9 cells had an inhibitory effect on cell migration ability. An up-regulation of LCN2 expression correlated with the downregulation of Hypoxia-inducible factor 1 alpha (HIF-1α) and carbonic anhydrase IX (CAIX). Ectopic expression of LCN2 suppressed the migration of oral cancer cells, which is dependent on CAIX expression. Our results suggested that plasma levels of LCN2 and LCN2/MMP-9 complex may be useful in non-invasive monitoring OSCC progression. Furthermore, LCN2 expression suppressed the migration ability of oral cancer cell lines, which may be dependent on the hypoxia-related factors expression.