2011-05-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647363摘要：生物標誌對於預測早期肺癌接受手術切除後的復發以及晚期肺癌藥物治療療效以被認知具有實際效用。但目前仍缺乏有用的生物標誌可作為肺癌早期診斷用途，而無法有效早期診斷是肺癌存活率持續低迷的重要原因。我們先期的研究，建立了一個高度表現岩藻醣基轉移酶基因的細胞株（A549F4A4），該細胞株在動物模式中，被證實在皮下接種後，會產生多處內臟轉移，尤其是肺臟。我們辨識A549F4A4細胞中許多岩藻醣化程度比較明顯的蛋白質，包括細胞溶解酶cathepsin D（CTSD）。研究發現CTSD會在肺腺癌有較多的表現量，而表現出叫多量CTSD的肺癌，較容易出現早期復發以及死亡。而利用肺癌病人的血清與尿液，我們也發現許多在肺癌體液出現的異常醣化表現的蛋白質，包括GM2AP蛋白，以及會表現出特殊sLex抗原的結合球蛋白（hptoglobin，Hp）。我們的研究發現診測血中的特殊sLex抗原可以有效鑑別肺癌。而進一步的研究發現，肝細胞因為受到肺癌細胞釋放出來的第六間白質（IL-6）而在結合球蛋白上產生sLex抗原之特殊修飾。本計畫的研究目的為利用臨床檢體以確認上述幾個生物標誌（CTSD，GM2AP，sLex Hp）在肺癌預後以及診斷的應用效益。本研究會收集大量的臨床檢體，並計畫以抗體開發出能快速與高量檢驗血液中上述生物標誌的試劑。而進一步瞭解上述生物標誌的生化合成機制以及生物行為的意義也是本研究的重要目標。<br> Abstract: Biomarkers are considered potentially useful in predicting recurrence after complete surgicalresection of early lung cancer, and in predicting treatment response to specific anticancertherapy in advanced stage lung cancer. However, the absence of a diagnosis biomarker forearly detection of lung cancer is one of the major reasons for low survival rate in lung cancerpatients. Previously, we developed a cell line (A549F4A4) which overexpressesfucosyltransferase IV (FucT4) and has high metastatic potential to visceral organs, especiallyto lung. Several proteins with aberrant fucosylation were identified in A549F4A4 cells,including Cathepsin D (CTSD). CTSD was found to be overexpressed in adencoarcinoma andcorrelated with a poor prognosis. Patients with tumor expressed higher amount of CTSD tendto had earlier disease relapse and shorter survival. We also demonstrated that specific aberrantglycosylation (GM2AP) and certain glycoproteins in the sera and urine of lung cancer patients.A unique posttranslational modification of sLeX on haptoglobin was identified in serum oflung cancer patient. Our preliminary data demonstrate that sLeX is an excellent discriminatebiomarker in late stage sera of lung cancer. Also, the data of cell model suggested that themodification of sLeX on haptoglobin is generated from liver cells which stimulated bycytokines (i.e. IL-6) produced by lung cancer cell. The objectives of this proposal are tovalidate the role of these biomarkers, CTSD, GM2AP and a unique posttranslationalmodification of sialyl lewis X (sLeX), in prognosis and diagnosis of lung cancer. We will alsodevelop the antibody-based assay for high through-put detection of sLeX Hp, GM2APand CTSD in sera of lung cancers. Validation of the clinical utilization in larger sample size isconsidered. To understand the biochemical mechanism and the biological meaning of thisbiomarker in lung cancer is worthwhile to address and will be important for clinical use.醣化岩藻醣化細胞溶解酶結合球蛋白sialyl lewis x醣抗原glycosylationfucosylationcathepsin Dheptoglobinsialyl lewis x