NRAGE Suppresses Metastasis Of Pancreatic Cancer And Melanoma In Vitro And In Vivo

Despite improvements in therapeutic strategies including surgicaltechniques as well as adjuvant therapies, pancreatic cancer and melanomacontinue to be formidable diseases and are associated with a very highincidence of fatality. The majority of patients are found to haveaggressive local invasion of adjacent structures and metastatic lesions.Hope for novel therapies originates from new treatment strategies thatattack specific steps of the metastatic cascade.NRAGE (Neurotrophin Receptor-interacting MAGE homolog) is arecently identified molecule belonging to the MAGE (melanoma antigen)protein family. The expression of most MAGE proteins is restricted tocancer cells; however, NRAGE is expressed in many normal tissues inearly development and adult stage. Recent experiments revealed thatNRAGE is downregulated in some types of cancers, which implicatedthat NRAGE is concerned with carcinogenesis.Many studies shew thatNRAGE can still be thought to be a very important mediator of apoptosisand cell proliferation. However, the precise function of NRAGE involvedin regulating tumor cell invasion and metastasis remains unknown.Now, we demonstrate the potential role of NRAGE to suppress tumor cell invasion and metastasis in pancreatic cancer and melanoma in vivoand in vitro systematically. At the same time, the molecular mechanismsthrough which NRAGE suppresses tumor cell invasion are exploredelementaryly in this paper.Our results show as follow:1. After Knocked down of NRAGE, PANC-1 cells exhibits a moremetastatic phenotype than the native cells, with downregulation ofepithelial proteins,such as E-cadherin, 13-catenin. These cellsunderwent an epithelial mesenchymal transition(EMT).2. In vitro,utilizing the transwell assay and wound-healing assay, wehave shown that overexpression of NRAGE to the pancreatic cancercell line PANC-1 strongly decreased mobility. However, it is difficultto explain that E-cadherin andβ-catenin were depressed, too. At thesame time, we found that extrinsic NRAGE can suppress expression ofintrinsic NRAGE.3. In vivo, NRAGE reduced the incidence of lung and liver metastasis ofB16-BL6 cells but the tumor growth of these cells.4. As measured by RT-PCR and zymography assay, Silence of NRAGEenhance MMP-2 expression and activity, whereas overexpression ofNRAGE suppress MMP-2 expression and activity.It could be one ofmolecular mechanisms that NRAGE suppresses invasion andmetastasis of pancreatic cancer and melanoma. In summary, here we show NRAGE suppresses invasion and metastasisof pancreatic cancer and melanoma in vitro and in vivo at multiple levels.Our findings also indicate that NRAGE represents a potential therapeutictarget for strategies designed to inhibit the progression of pancreaticcancer and melanoma.