The Study Of Molecular Mechanism Of P53 Regulating Metastasis Of Colorectal Cancer By Activating Fascin

P53 mutation is known to contribute to cancer progression.Fascin is an actin-bundling protein and has been recently identified to promote cancer cell migration and invasion through its role in formation of cellular protrusions such as filopodia and invadopodia.However,the relationship between P53 and Fascin is not understood.Aim To study the relationship,as well as the mechanism,of P53 and the Fascin expression with the survival time in the patients with colorectal adenocarcinomas.Methods Patients diagnosed with colorectal cancer between February 2004 to June 2006 were included in this study(n=75,Patients with pre-operative chemotherapy or radiotherapy were excluded).P53 mutations were tested by sequencing and expressions of P53,Fascin,E-cadherin and NF-?B were detected by Immunohistochemistry.Cell structure and expressions of Fascin,E-cadherin were observed by immunofluorescence.The tumor migration ability were tested by Tranwell assay.Tumor metastasis related proteins including Fascin,NF-?B,E-cadherin,N-cadherin and Vimentin were tested by Western blot.IKK? and IKK? were tested by real-time PCR.P53/P65 were knocked in and knocked out by adenovirus and RNA interference irrespectively.Results the P53 mutation correlated with high NF-?B,Fascin and low E-cadherin expression was shown to contribute to poor overall survival in patients with colorectal cancer.Wild-type P53 could inhibit NF-?B activity that repressed the expression of Fascin and cancer cell invasiveness.In contrast,in P53-deficient cells,NF-?B activity was enhanced and then activation of NF-?B increased the expression of Fascin.In further analysis,we showed that NF-?B was a key determinant for P53 deletion-stimulated Fascin expression.Inhibition of NF-?B/P65 expression by pharmacological compound or P65 siRNA suppressed Fascin activity in P53-deficient cells.Moreover,restoration of P53 expression decreased the activation of Fascin through suppression of the NF-?B pathway.Conclusion these data suggest that a negative-feedback loop exists,whereby P53 can suppress colorectal cancer cell invasion by inhibiting the NF-KB-mediated activation of Fascin.