口腔癌在印度、巴基斯坦、孟加拉共和國、斯里蘭卡與台灣等國家有極高的盛行率，且致死率更是逐年升高。抽菸、酗酒與嚼檳榔被認為是主要的致病因子。儘管過去已有研究發現許多口腔癌相關的生物標記，但能夠真正輔助臨床診斷的非常少。因此，發展出有效的口腔癌生物標記，對於目前口腔癌的發展趨勢來說，是非常緊迫的。在先前的研究中，我們發現口腔癌組織與血漿中，核心岩藻糖(core fucose)及其酵素岩藻糖轉移酶8(Fucosyltrnsferase 8, FUT8) 的含量，都比正常人高出許多。因此，本研究希望能利用醣蛋白質體(glycoproteomics)方法，找出血中帶有核心岩藻醣基化之醣蛋白作為有效的口腔癌生物標記。首先，將所有血漿樣本注入橙黃網孢盤菌(Aleuria aurantia)凝集素親和層析管柱，純化出帶有核心岩藻醣基化之蛋白，再利用電泳法及液相層析串聯式質譜儀分析。最終找出了14種血漿醣蛋白，並以西方墨點法分析血中含量，其中，藍胞漿素(Ceruloplasmin)、血紅素結合蛋白(Haptoglobin)、富亮氨酸α2醣蛋白1(Leucine-rich alpha-2 glycoprotein 1, LRG1)在口腔癌病人血漿中濃度上升，而脂蛋白元A-I(Apolipoprotein A-I)及脂蛋白元A-IV(Apolipoprotein A-IV)則有下降趨勢。接著，我們增加樣本數並利用酵素免疫分析法作確認，發現脂蛋白元A-IV不論是在血中真實濃度，或與血中總蛋白之相對濃度(Apo A-IV/Total protein)，在口腔癌血漿中都有下降的趨勢；富亮氨酸α2醣蛋白1即使在血中真實濃度沒有明顯變化，但在血中總蛋白之相對濃度(LRG1/Total protein)則呈現明顯上升趨勢。在ROC曲線(receiver operating characteristic curve)分析中，我們發現結合脂蛋白元A-IV與富亮氨酸α2醣蛋白1/總蛋白比值，在分辨口腔癌病患的表現上有良好的敏感度與特異度。此外，脂蛋白元A-IV在驗證組別中，也同樣有良好的分辨能力。因此，根據本研究結果，我們認為脂蛋白元A-IV與富亮氨酸α2醣蛋白1是有潛力的口腔癌生物標記蛋白，在未來也許能發展出有效的方法，幫助口腔癌的篩檢與診斷。

Oral cancer with high incidence rate is occurring in many countries including India, Pakistan, Bangladesh, Sri Lanka and Taiwan. Smoking, alcoholism, and betel nuts chewing are considered the main risk factors for oral cancer. Further, oral cancer caused deaths are also increased year by year. Although several oral cancer associated biomarkers have been reported, very little of useful biomarkers have been identified for clinical diagnosis. Therefore, to investigate oral cancer specific biomarkers is urgently needed. We previously analyzed oral cancer tissue and plasma glycomes and found that mRNA level of FUT8 and core-fucosylation level of plasma proteins were both increased in oral cancer patients compared to normal group. In this study, we aim to discover novel core-fucosylated glycoprotein biomarkers for oral cancer diagnosis by glycoproteomic approaches. First, all of the plasma samples were subjected into AAL (Aleuria aurantia lectin) affinity chromatography. The core-fucosylated proteins were collected and applied for LC-MS/MS after electrophoresis. Finally, 14 proteins were identified and the expression levels of the proteins in plasma were verified by western blot. The expression levels of some glycoproteins were elevated in oral cancer group such as ceruloplasmin, haptoglobin, and leucin-rich alpha-2-glycoprotein 1 (LRG1). However, some glycoproteins were decreased in cancer group including apolipoprotein A-I (apo A-I) and apolipoprotein A-IV (apo A-IV). Further verified by ELISA analysis with larger sample size, we found that the level of apo A-IV were decreased in plasma level accompanied with a decreased apo A-IV/total protein ratio in oral cancer patients. LRG1/total protein ratio was found to elevate while plasma level of LRG1 was found no difference in oral cancer plasma compared to normal group. ROC curve analysis showed well diagnosis performance when combining Apo A-IV level and LRG1/total protein ratio. Moreover, we validated the plasma levels of the apo A-IV with validation group and obtained good diagnostic performance as well. Taken together, apo A-IV and LRG1 with good performance in detecting oral cancer can become useful biomarkers and have potential to establish a useful methodology for oral cancer screening.

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