Potential Roles Of Twist And P53 In Resveratrol-induced Differention And Aptosis Of Medulloblastoma Cells

Medulloblastoma is the most common malignant childhood tumor of central nervous system. It belongs to primitive neuroectodermal tumor (PNET), predominantly arising in the cerebellum and 4th ventricle, often accompanied by the ventricular ependyma penetrated the bottom of the brain stem. As the quite important function of the brain, traditional radiotherapy, chemotherapy and surgery is difficult to completely eradicate and those treatments often seriously affect the live quality of children. Therefore looking for reliable efficacy and low toxicity of therapeutic drugs have considerable clinical application values. Resveratrol (3,5,4'-trihydroxy-Anti-Diphenyl Ethylene), fat-soluble compounds, widespread in seed plants especially rich in the fresh skin of red grapes. Studies show that resveratrol has a wide range of functions such as anti-cardiovascular disease, anti-mutagenic, anti-bacterial, anti-cancer, inducing cell apoptosis and protection of the central nervous system. Our previous studies found that resveratrol can induce differentiation and apoptosis of medulloblastoma in dose-dependent manner in vitro, resveratrol-induced medulloblastoma differentiation and apoptosis related to its regulation of STAT3, Wnt, Notch and Shh signaling pathways and the expression level of other relevant factors. Therefore continuous discussion the molecular mechanism of resveratrol induced differentiation and apoptosis of medulloblastoma, looking for the anti-cancer targets of resveratrol in order to screening the potential therapeutic targets in medulloblastoma have significant clinical values. Twist, an important transcriptional factor of the basic helix loop helix (bHLH) family, has been recently reported to play an important role in tumorigenesis of human cancers. Twist over-expression was found in many kinds of human cancers such as glioma, neuroblastoma, melanoma, breast cancer, gastric cancer, prostate cancer and so on. The high expression of Twist promotes tumor cells proliferation, anti-apoptosis, invasion and metastasis, inhibiting the expression of tumor suppressor p53 and its function.There are no research on the roles of Twist and p53 in medulloblastoma right now. Therefore, in this paper we take Twist and p53 as the starting point to analysis the expression status of Twist and p53 in medulloblastoma in order to looking for the potential therapeutic targets of medulloblastoma for clinical treatment.Objective:To detect the expression status of transcriptional factors Twist and p53 in medulloblastoma, analysis the influence of resveratrol to the expression of Twist and p53 during differentiation and apoptosis of medulloblastoma cell line UW228-2 induced by resveratrol, discuss the molecular mechanisms of differentiation and apoptosis of medullo-blastoma induced by resveratrol, so as to provide guidance to the better clinical treatment of medulloblastoma.Methods:Test the expression levels of Twist and p53 in 106 clinically collected medulloblastoma cases, And, by method of Immunocytochemistry (ICC) stainings, RT-PCR and Western Blot, check the differentiations of genic expression levels of Twist and p53 in human medulloblastoma cell line UW228-2 after being treated with resveratrol, and further study the correlation between Twist, p53 and resveratrol induced differentiation and apoptosis of medulloblastoma.Results:Immunohistochemical staining show a relatively high level of Twist expression in medulloblastoma tissues with a expression rate of 77.03% and 54.05% in cytoplasm and nucleus respectively; while the expression of p53 was low with the rate of 28.13% and 34.38% respectively. RT-PCR, immunocytochemistry (ICC) and Western Blot all show the down-regulated expression of Twist in cell line UW228-2 after being treated with resveratrol, while the expression of p53 was significantly up-regulated, accompanied by the nuclear translocation.Conclusion:The expression level of Twist was relatively high in medulloblastoma tissues while p53 was low; Resveratrol has the ability of down regulation the expression of Twist in medulloblastoma cell line UW228-2, while increasing the expression level of p53; Resveratrol can induce the differentiation and apoptosis of medulloblastoma possibly related to its ability to regulate the expression of Twist negatively and p53 positively; the high expression of Twist in medulloblastoma may supress the anticancer function of p53.