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標題: 利用蛋白質體技術探討人類唾液之口腔癌生物標誌以及抗口腔癌藥物之分子機制
Study on human salivary biomarkers of oral cancer and molecular mechanisms of anti-oral cancer agents using proteomic technology
作者: 周于楨
Yu-Jen Jou
關鍵字: 口腔癌;蛋白質體;生物標識;細胞凋亡;oral cancer;proteomic;biomarker;γ–Bisabolene;apoptosis
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在全球,口腔癌(Oral squamous cell carcinoma, OSCC)的死亡率有逐漸上升的趨勢,另外在台灣,也是公共衛生問題之一。本篇研究目的在於使用基質輔助雷射脫附游離飛行時間質譜以及奈流液相層析質譜技術,利用非侵入性方法提取口腔癌患者唾液探討人類口腔癌唾液中蛋白以及胜肽的生物標誌,以及研發抗口腔癌藥物,瞭解其抗癌分子機制。
本研究於民國97年到101年間,收集到正常組27人以及口腔癌患者實驗組106人的唾液。利用C-8微粒磁珠以及基直輔助雷射脫附游離飛行時間質譜,找出唾液中的胜肽,接著利用ClinProTools軟體分析,找出有差異之胜肽質量2918.57 Da。進一步MS/MS鑑定此胜肽片段,得到ZNF510的胜肽。經由酵素免疫聯結吸附分析以及免疫組織染色發現,ZNF510在唾液中的ㄎ實驗組的表現比正常組高。根據areas sections receiver operating characteristic (AUROC)曲線,T1+T2所占面積比為0.95,因此得知ZNF510可以檢測早期的口腔癌。另外利用奈流液相層析質譜分析,人類口腔癌唾液之小分子(10 kDa~15 kDa)蛋白標誌,得到S100A8作為檢測T3+T4之口腔癌生物標誌。接下來使用西方墨點法、酵素免疫聯結吸附分析以及免疫組織染色進一步證實,S100A8在口腔癌晚期(T3和T4)的表現較高。根據AUROC曲線得知,在口腔癌唾液中S100A8有較高準確度,因此S100A8蛋白和口腔癌唾液為正相關。由此可知ZNF510胜肽以及S100A8蛋白可作為檢測口腔癌之生物標誌。
γ –Bisabolene可造成癌細胞粒線體膜電位下降,來活化caspase 3/9誘導口腔癌細胞凋亡。根據奈流液相層析質譜得到,正調控的磷酸化蛋白為p53、protein phosphatases 1 (PP1)以及ERK1/2,另外負調控蛋白為histone deacetylase 2 (HDAC2)。使用GeneGo MetaCore軟體得知,γ –Bisabolene可經由PP1-HDAC2-p53以及ERK1/2-p53路徑誘導細胞凋亡,γ –Bisabolene亦可增加p53的乙醯化以及調控細胞凋亡基因之表現。此外在γ–Bisabolene誘導Ca9-22以及SAS細胞凋亡中,加入PP1 inhibitor-2抑制劑會恢復HDAC2的磷酸化、降低p53的乙醯化以及PUMA mRNA的表現量。在γ–Bisabolene誘導Ca9-22以及SAS細胞凋亡中,加入MEK和ERK1/2抑制劑,也會抑制PUMA mRNA的表現量。根據上述結果得知,γ–Bisabolene經由粒線體、PP1-HDAC2-p53以及ERK1/2-p53路徑誘導細胞凋亡。動物實驗中,γ–Bisabolene亦可有效控制口腔癌細胞增生以及腫瘤縮小,可開發作為抗口腔癌之藥物。

Oral squamous cell carcinoma (OSCC) is a worldwide malignant that has emerging as a public health problem in Taiwan. Saliva is a non-invasive sample with good potential to investigate biomarkers for early diagnosis of oral cancer.
In our project, we collected saliva samples from 27 health controls and 106 OSCC patients during the period 2008-2012. Using C8-magnetic beads, MALDI-TOF MS technology and the ClinProTools software, we identified a peptide of zinc finger protein 510 (ZNF510) from a 2918.57 Da signal that distinguished OSCC patients from controls. Results from enzyme-linked immunosorbent assay (ELISA) and immuno-histochemical methods, we found ZNF510 peptide level was significantly increased in the saliva (P<0.001) and higher in the tissue sections of OSCC patients, in comparison with the health donors. The value of areas under receiver-operating characteristic (AUROC) curve of OSCC at stages T1+T2 was 0.95, indicating high level of accuracy for the ZNF510 peptide-based ELISA in detection of early stages of OSCC patients. By proteomic approaches, ZNF510 was identified as an oral cancer biomarker for early detection. In addition, analysis of low molecular weight salivary proteins (10 to 15 kDa) via the nanoLC-MS/MS method, we isolated the salivary S100A8 proteins as potential biomarkers in T3+T4 stages of OCSS, respectively. Results from western blotting, ELISA and immuno-histochemical methods, we found strongly up-regulation of S100A8 levels in late stage in saliva and tissues of OSCC. Importantly, salivary S100A8 protein was positively correlated to tumor size stage of OSCC, meanwhile the AUROC curve of S100A8-based ELISA exhibited high level of accuracy. Collectively, our data suggest that both ZNF510 and S100A8 are potential salivary biomarkers for the diagnosis of developing OSCC.
In our second project, we identified a cardamom-derived compound, γ-bisabolene, which possesses antiproliferative activities against of OSCC in vitro and in vivo. We found γ-bisabolene can lead to apoptosis of OSCC cell lines (Ca9-22 and SAS) by activating caspases-3/-9 as well as reducing mitochondrial membrane potential. Using nanoLC-MS/MS, western blotting and real-time RT-PCR methods to analyze the phosphoproteome profiling of γ -bisabolene-treated OSCC cells, results indicated the enrichment of phosphorylated ERK1/2, protein phosphatases 1 (PP1), and p53 and the reduction of phosphorylated histone deacetylase 2 (HDAC2) during apoptosis. In addition, by using Metacore GeneGo analysis, our results proposed the γ-bisabolene-induced apoptosis might involve in PP1-HDAC2-p53 and ERK1/2-p53 pathways. γ-bisabolene was found to enhance acetylation of p53 that increased the expression of p53-regulated apoptotic genes. PP1 inhibitor-2 increased the phosphorylation of HDAC2 and decreased acetylation of p53 and PUMA gene expression in γ-bisabolene treated Ca9-22 and SAS cells. ERK and MEK inhibitors reduced the expression of PUMA gene after treating Ca9-22 and SAS cells with γ-bisabolene. The results confirmed that the treatment of oral cancer cells with γ-bisabolene induced mitochondria-mediated apoptosis via PP1-HDAC2-p53 and ERK1/2-p53 signal pathways. Our study suggests that γ-bisabolene maybe a potential anti-tumor agent of human oral cancer.
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