HMG-CoA reductase inhibitors suppress EGF-induced migration in anaplastic thyroid carcinoma

• Main Authors: Jr-Jiun Liu, 劉芷君
• Other Authors: Wen-Bin Zhong
• Format: Others
• Language: zh-TW
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/uvnytr

碩士 === 臺北醫學大學 === 醫學科學研究所 === 102 === Anaplastic thyroid carcinoma (ATC) is the most malignant thyroid cancer. A majority of patients can only survive for 3 to 5 months after diagnosed. There are various treatment options for ATC including surgery, chemotherapy, radiation therapy and etc., however, none of them can significantly improve ATC survival rate. Recent research reports have shown that EGFR expression is elevated in thyroid tissue section from ATC patients. In addition , EGFR expression is found positively correlated with the malignancy of ATC. Inhibiting the activation of EGFR might become another therapeutic approach in ATC. Statins are a class of HMG-CoA reductase inhibitors and can inhibit the function of EGFR and its dimerization. Statins have being used as an adjuvant chemotherapy to inhibit cell proliferation and promote apoptosis in breast cancer. However, their roles in ATC cells migration still remain unclear. In this study, we hypothesized that HMG-CoA reductase inhibitors (simvastatin、atorvastatin and pravastatin) can inhibit cancer cell migration in ATC. Wound-healing migration assay and Transwell migration assay in human ATC cell lines (SW1736, 8305C) were used to examine whether EGF can promote cell migration despite of their different EGFR expression and doubling time. We also compared the efficacy of statins in the inhibition of ATC cells migration. EGF induced concentration- dependent migration in both cell lines (SW1736, 8305C). The effect of statins (simvastatin, atorvastatin and pravastatin) on EGF-induced ATC cell migration was evaluated by the administration of EGF (20 ng/ml). Results from wound-healing migration assay were further confirmed by Transwell migration assay in the inhibition of ATC cell migration by statins. Our previous results showed that Cysteine-rich protein 61 (Cyr61), a secretory protein, is downstream to EGF signaling pathway. Other studies also showed that the expression of Cyr61 was abnormally elevated in thyroid cancer. We further examined whether statins will also affect Cyr61 expression. We found that Cyr61 expression was inhibited by statins (10μM) in ATC. Also, when Cyr61 was knocked-down by its si-RNA , the ability of ATC cell migration was reduced; whereas, overexpressed Cyr61 promoted ATC cell migration. Furthermore, the expression of FAK and Paxillin, which are well known downstream protein for EGF, was also up-regulated by EGF, and was inhibited by statins. Therefore, we thought Cyr61, FAK and Paxillin were involved in the regulation of EGF-induced ATC cell migration. In short, all of these three proteins were involved in ATC cell migration; while, HMG-CoA reductase inhibitors (simvastatin, atorvastatin and pravastatin) can suppress ATC cells migration by inhibiting expression of these three proteins.