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標題: 褪黑激素抑制胃癌生長及腹膜轉移機轉之探討
The Mechanism of Melatonin Inhibits Tumor Growth and Peritoneal Dissemination in Gastric Cancer Cells
作者: 吳昇懋
Wu, Sheng-Mao
Contributors: 許美鈴
生物醫學研究所
關鍵字: 胃癌;褪黑激素;Calpain;NFκB;C/EBPβ;腹膜轉移
gastric cancer;Melatonin;calpain;C/EBPβ;NFκB;peritoneal dissemination
日期: 2012
Issue Date: 2013-11-18 11:04:55 (UTC+8)
Publisher: 生物醫學研究所
摘要: 內質網壓力所導致的細胞凋亡以及抑制腫瘤在腹膜中的擴散已知與
癌症的發展有密切的關係。褪黑激素是由大腦內的松果體所分泌的一種荷爾蒙。過去的研究指出褪黑激素具有清除自由基和抗氧化的活性,並且也可能具有抑制腫瘤的功用。然而,褪黑激素是否能抑制胃癌生長以及癌細胞在腹膜中擴散的情況,目前還是未知且尚待釐清的。本篇研究使用了各種活體內、活體外及生物體外等實驗系統,來多方驗證褪黑激素抑制腫瘤生長以及腫瘤在腹膜中擴散的效用。從活體外的實驗結果我們發現褪黑激素能有效抑制癌細胞增生、細胞群簇的形成、細胞的移動能力和金屬蛋白酶的活性等。在裸鼠腫瘤異體移植試驗中,褪黑激素明顯抑制了腫瘤生長,而使用正子電腦斷層掃描(PET/CT)也清楚驗證褪黑激素有效的減少腫瘤在腹膜中的擴散轉移。此外,使用小鼠皮下matrigel plug 技術、大鼠主動脈環實驗和人類臍靜脈內皮細胞血管新生實驗,也都發現褪黑激素能有效抑制血管新生。從電泳遷移率實驗(EMSA)和染色質免疫沉澱法(CHIP assay)的實驗結果我們更進一步證實褪黑激素能有效降低轉錄因子NFκB 和C/EBPβ的轉錄作用並減少兩個蛋白間的交互作用。另一方面,褪黑激素能夠造成內質網壓力並增加細胞中Calpain 的蛋白表現和活性,造成其他蛋白質的降解。在使用了Calpain 的抑制劑和轉染siRNA 後發現,褪黑激素所抑制的NFκB 和C/EBPβ調控的COX-2 的表現會被有效的逆轉。這些實驗結果說明了褪黑激素能有效的抑制胃癌細胞生長及在腹膜中的擴散轉移,提供其在治療胃癌上具有高度應用的潛力。
Endoplasmic reticulum stress-regulated cell apoptosis and dampened peritoneal dissemination is implicated in the progression of cancer. Melatonin (N-acetyl-5 methoxytryptamine), a hormone produced in the brain by the
pineal gland, has previously been reported to antioxidant activity and oncostatic properties in a wide variety of tumors. Whether Melatonin inhibits the tumor growth and peritoneal dissemination of gastric cancer remains enigma. We tested the effects of Melatonin on antitumor activity and
peritoneal dissemination using in vivo, ex vivo and in vitro assay systems. In vitro study, we found that Melatonin inhibited proliferation, colony formation, migration and gelatin zymography were observed. In xenograft gastric tumor mouse model, Melatonin significantly inhibited tumor burden and peritoneal dissemination detected by PET/CT technique. Melatonin also effectively inhibited the angiogenesis determined by mouse matrigel plug assay, rat aortic ring endothelial cell sprouting assay, and endothelial cell tube formation assay.
Furthermore, Melatonin efficiently abolished physical interaction and mutual functional between C/EBPβ and NFκB by EMSA or CHIP assay, which was simultaneously correlated with the up-regulation of the activity and protein
expression of calapin, result in protein reduction. Calpain inhibitor and siRNA transfection significantly reversed the Melatonin-increased cleavage of C/EBPβ and NFκB regulated COX-2 expression and ER stress marker. These findings suggest that Melatonin is a novel and potent inhibitor for tumor growth and peritoneal dissemination of gastric cancer, which supports the application potential of Melatonin on gastric cancer therapy.
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