Abstract
The Wnt/β-catenin signalling pathway is activated in pancreatic cancer initiation and progression. Dickkopf-related protein 3 (DKK3) is a member of the human Dickkopf family and an antagonist of Wnt ligand activity. However, the function of DKK3 in this pathway in pancreatic cancer is rarely known. We examined the expression of DKK3 in six human pancreatic cancer cell lines, 75 pancreatic cancer and 75 adjacent non-cancerous tissues. Dickkopf-related protein 3 was frequently silenced and methylation in pancreatic cancer cell lines (3/6). The expression of DKK3 was significantly lower in pancreatic cancer tissues than in adjacent normal pancreas tissues. Further, ectopic expression of DKK3 inhibits nuclear translocation of β-catenin induced by hypoxia in pancreatic cancer Bxpc-3 cell. The forced expression of DKK3 markedly suppressed migration and the stem cell-like phenotype of pancreatic cancer Bxpc-3 cell in hypoxic conditions through reversing epithelial-mesenchymal transition (EMT). The stable expression of DKK3 sensitizes pancreatic cancer Bxpc-3 cell to gemcitabine, delays tumour growth and augments gemcitabine therapeutic effect in pancreatic cancer xenotransplantation model. Thus, we conclude from our finding that DKK3 is a tumour suppressor and improved gemcitabine therapeutic effect through inducing apoptosis and regulating β-catenin/EMT signalling in pancreatic cancer Bxpc-3 cell.
Highlights
The Wnt/b-catenin signalling pathway is activated in pancreatic cancer initiation and progression
Methylation-specific PCR analysis revealed that Dickkopf-related protein 3 (DKK3) methylation were detected in pancreatic cancer cell lines Aspc-1, Bxpc-3, CFPAC-1, which were in agreement with the result of Western blotting (Fig. 1B)
The expression of DKK3 was significantly lower in pancreatic cancer tissues than in adjacent normal pancreas tissues (Fig. 1C)
Summary
The Wnt/b-catenin signalling pathway is activated in pancreatic cancer initiation and progression. Dickkopf-related protein 3 (DKK3) is a member of the human Dickkopf family and an antagonist of Wnt ligand activity. The function of DKK3 in this pathway in pancreatic cancer is rarely known. Ectopic expression of DKK3 inhibits nuclear translocation of b-catenin induced by hypoxia in pancreatic cancer Bxpc-3 cell. We conclude from our finding that DKK3 is a tumour suppressor and improved gemcitabine therapeutic effect through inducing apoptosis and regulating b-catenin/EMT signalling in pancreatic cancer Bxpc-3 cell. Till date, there is rare information as to the expression of DKK3 and its function in EMT and chemotherapy in pancreatic cancer. Our results demonstrated that DKK3 regulated EMT and improved gemcitabine therapeutic effect in pancreatic cancer
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