甲狀腺癌（TC）是很常見的內分泌性的惡性腫瘤，並且其罹患率在全世界正迅速增加。甲狀腺未分化癌（ATC）是甲狀腺癌中最具有侵略性及嚴重的惡性腫瘤。甲狀腺未分化癌患者的預後相當的差，確診後的平均存活時間小於6個月。研究報告指出甲狀腺癌中激活突變的BRAF基因約佔有60％，而突變的BRAF基因與預後情形差、轉移和復發有關。在本研究中，我們試圖透過2D-DIGE凝膠的蛋白質體學的方法，探討在甲狀腺癌中（BRAF抑制劑）的生物標誌物。甲狀腺未分化癌細胞株是長時間的培養在低濃度的cisplatin, doxorubicin和PLX4032藥物中，以建立穩定的抗藥性細胞株，並透過LC / MS / MS蛋白質體學方法進一步分析。我們的研究結果發現，甲狀腺未分化癌細胞用PLX4032長時間處理後會活化GSTA1表達。GSTA1可以作為一個對PLX4032化療抗藥性的生物標誌物，增加甲狀腺未分化癌的治療效果，提高甲狀腺癌患者的預後。

Thyroid carcinoma (TC) is the most common endocrine malignancy and is one of the most rapidly increasing human cancers worldwide. Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid gland malignancy. Patients with anaplastic thyroid cancer have a very poor prognosis, with a mean survival time of less than 6 months from the time of diagnosis.(Larkin et al.) Activating mutations of BRAF were reported recently in 60% of thyroid cancer, and BRAF mutation has been associated with poor prognosis, more cancer invasiveness, metastasis and recurrence in patients with thyroid cancer. In the present study, we sought to investigate the chemoresistance biomarkers for cisplatin, doxorubicin, PLX4032 (a specific BRAF inhibitor) in thyroid cancer by using 2D-DIGE gel based proteomic approach. Anaplastic thyroid carcinoma cell lines were first cultured and long-term maintained in low concentration of cisplatin, doxorubicin, PLX4032 in order to establish chemoresistant stable clones, and further analyzed and characterized chemo-resistant associated proteins by using capillary LC/MS/MS proteomic method. Our results discovered that activated expression of GSTA1 after PLX4032 treatment in ARO cells. The identification of novel chemoresistant biomarker to PLX4032 may increase effectiveness of anaplastic thyroid cancer treatment, and improve the prognosis of thyroid cancer patients.

Abstract in Chinese ---------------------------------------------------------- ⅱ
Abstract in English ---------------------------------------------------------- ⅲ
Abbreviation ------------------------------------------------------------------ ⅳ
Introduction ------------------------------------------------------------------- 1
Materials and Methods ---------------------------------------------------- 6
Results ------------------------------------------------------------------------- 14
Discussion -------------------------------------------------------------------- 20
Figures and Tables ----------------------------------------------------------- 23
References -------------------------------------------------------------------- 45

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