| 摘要: | 甲狀腺未分化癌 (ATC) 是最難治療的甲狀腺癌，也是存活期最短的癌症之一，傳統的治療方式包括手術、放射線治療、化學治療或其合併治療，效果非常不理想，病患經診斷後平均只能存活三個月。有鑑於此，新的分子標靶藥物研究與治療方式，在甲狀腺未分化癌的治療上，是一個必要的研究課題。甲狀腺未分化癌會表現過量的表皮生長因子 (EGF)，這與甲狀腺未分化癌的致病機轉有密切相關，且甲狀腺癌的患者通常會大量表現Cyr61，根據研究數據顯示，表皮生長因子可以誘導的Cyr61表現，進而導致在人類甲狀腺未分化癌細胞的細胞遷移增加；在血漿可達到的濃度之下，PPARγ配體之降血糖藥物troglitazone (5 μM) 與降血脂藥物lovastatin (1 μM) 合併使用，可以在無細胞毒性 (cytotoxicity) 的情況下，抑制表皮生長因子所誘導的甲狀腺未分化癌細胞遷移。Troglitazone與lovastatin合併使用也改變了EMT相關的基因的表達，具體而言，表皮細胞蛋白E-cadherin表現增加和間質細胞蛋白vimentin表現減少。Troglitazone與lovastatin合併治療降低了表皮生長因子所誘導的絲狀偽足 (filopodia) 的數目，且絲狀偽足被認為是參與遷移的重要因子之一；合併治療也顯著抑制表皮生長因子誘導的Cyr61 mRNA和蛋白表現量以及在細胞培養基中的分泌量。除此之外，表皮生長因子誘導的Cyr61表現，主要是透過兩個關鍵信號分子CREB和ERK的磷酸化所導致，而在甲狀腺未分化癌，troglitazone與lovastatin合併治療減少CREB和ERK的磷酸化。進一步的使用冷光的表現量來測試Cyr61啟動子的活性，該合併治療顯著抑制Cyr61的啟動子 (promoter) 活性，而且也抑制了重組蛋白Cyr61所引起的細胞遷移。經由以上結果得知，低劑量的Troglitazone與lovastatin合併治療，可以有效的抑制表皮生長因子所誘導的CREB和ERK磷酸化，降低Cyr61的表現及分泌量，進而減少甲狀腺未分化癌細胞遷移。此種合併治療在轉移性甲狀腺未分化癌提供了一種新的治療策略，在未來的甲狀腺癌研究中具有極大的潛力。
Anaplastic thyroid cancer (ATC) is among the most aggressive types of malignant cancer with extremely short survival and poor prognosis. Conventional treatments for ATC include surgery, radiation therapy, chemotherapy, or combination therapy. Despite multimodality approaches, ATC still carries a poor prognosis. After the patients are diagnosed, the average survival rate is only three months. Therefore, it is important to develop therapeutic strategy for ATC. Epidermal growth factor (EGF) plays a crucial role in the pathogenesis of ATC, and patients with thyroid carcinoma typically exhibit increased cysteine-rich protein 61 (Cyr61). According to the data, EGF can induce cell migration through the induction of Cyr61 in human ATC cells. The inhibitory effects of combined treatment with the peroxisome proliferator-activated receptor-γ (PPARγ) ligand troglitazone and the cholesterol-lowering drug lovastatin at plasma achievable concentrations were determined on ATC cell migration. Troglitazone (5 μM) and lovastatin (1 μM) combined treatment exhibited no cytotoxicity but significantly inhibited EGF-induced migration, as measured using wound healing and Boyden chamber assays. Combined treatment with troglitazone and lovastatin altered the epithelial-to-mesenchymal-transition (EMT) -related marker gene expression of the cells; specifically, upregulating E-cadherin expression and downregulating vimentin expression. Moreover, cotreatment reduced the number of EGF-induced filopodia, which is involved in migration, and significantly inhibited EGF-induced Cyr61 mRNA and protein expression as well as Cyr61 secretion. In addition, the phosphorylation levels of two crucial signaling molecules for EGF-induced Cyr61 expression, the cAMP response element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), were decreased in ATC cells cotreated with troglitazone and lovastatin. By transition transfection assay, we found that the combined treatment significantly suppressed the EGF-induced Cyr61 promoter activity. The cotreatment also inhibited the human recombinant Cyr61-induced migration in the ATC cells. These results suggest that combined treatment of a low-dose of troglitazone and lovastatin effectively inhibits EGF-induced CREB and ERK phosphorylation, and reduces Cyr61 expression and secretion, thereby decreasing ATC cell migration. Such combination therapy offers a new treatment strategy in metastatic ATC. In the future, it has potential in thyroid cancer research. |
