| Summary: | 碩士 === 國立中興大學 === 生物醫學研究所 === 106 === Melatonin is a well-known indolamine hormone in the pineal gland shows a wide range of physiological and pharmacological function, including anticancer activity. In this study, we investigated the effect of Melatonin on peritoneal dissemination thwarts the gastric cancer cells and explored the role of Protease-activated receptor-1 (PAR-1) signaling in this process. First, PAR-1 expression was associated with lymph node and distant metastasis in patients with gastric cancer and was correlated with cliniclpathological pattern. In experimental xerography study, we found that Melatonin treatment led to a markedly decrease animal peritoneal dissemination model by PET/CT tomography. Importantly, Melatonin markedly reduced PAR-1 activity and protein expression by western blotting in animal. Additonally, Melatonin exhibited potent anticancer activity in vitro, as evidenced by of the cell adhesion, migration, epithelial-to-mesenchymal transition(EMT) marker and increases in the calpain activity and ER stress in gastric cancer cells. Moreover, Melatonin set out to evoke dissociation of CEBPβ/PPARγ interaction and further enhanced Calpain-10 and CEBPβ interaction resulted in enhancement of E-cadherin expression and increasing of interaction with β-catenin, Gene silencing of Calp-10 completed abolished above-mention effects. Furthermore, the inhibition of PAR-1 signaling using PAR-1 siRNA or pharmacological inhibitor completely abolished cancer cell metastasis and animal peritoneal dissemination. In summary, these data indicate that Melatonin is a potential suppressor of gastric cancer peritoneal dissemination by the targeting of PAR-1 signaling and progression through the activation of the Calpain-10/CEBPβ/PAR-1 signaling pathway and may act a new therapeutic target for gastric cancer.
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