P-0033 - Novel mechanism of Wnt signalling activation mediated by Dickkopf-1 methylation in pancreatic cancer
|Date||28 June 2014|
|Event||World GI 2014|
|Topics|| Pancreatic Cancer
|Citation||Annals of Oncology (2014) 25 (suppl_2): ii14-ii104. 10.1093/annonc/mdu165|
Q. Xu, J. Lei, L. Sheng, X. Chen, Q. Ma, W. Duan
Wnt signalling is a highly conservative signaling pathway. The abnormal activation of the pathway has an important role in cell fate determination, tissue patterning and tumorigenesis in pancreatic cancer, but the mechanisms of the Wnt pathway activation are poorly understood. Dickkopf (Dkk) is an antagonist, which inhibits the Wnt pathway. In this study, we report a novel mechanism of Wnt signalling activation mediated by Dickkopf-1 methylation in pancreatic cancer.
The clinical and pathological features of 45 formalin-fixed pancreatic cancer specimens and 8 normal pancreases as controls were performed to analyze the relation of DKK 1 abnormal methylation and the expression of ß-catenin in pancreatic cancer. qRT-PCR and Western-blot and Immunohistochemistry were used to detect the difference of the expression and location of ß-catenin and DKK 1 between the pancreatic cancer and normal pancreases. Gene mutations of ß-catenin EXON3 are performed by Gene sequencing analysis. The DKK 1 promoter methylation in pancreatic cancer tissues is detected by MSP.
The expression of ß-catenin was highly expressed in Pancreatic cancer tissues at gene and protein level, and the ß-catenin transported and accumulated into the cytoplasm and nucleus. We found that 24 cases existed significantly methylation of DKK 1 gene promoter, but not the mutations of -catenin EXON3. The results of Spearman analysis demonstrated that there is a negative correlation between high DKK 1 gene promoter methylation and the abnormal ß-catenin expression. Compared with the normal tissue, the level of DKK 1 gene promoter methylation and the expression of ß-catenin in cytoplasm and nucleus were significant higher in pancreatic cancer tissues.
The abnormal activation of Wnt/ß-catenin signaling in Pancreatic cancer is due to the DKK 1 gene promoter methylation, but irrelevant with the mutation of ß-catenin EXON3. Our findings might provide a new biological target for the therapy of pancreatic cancer in the future.