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Background:
Protein Tyrosine Kinase 6 (PTK6) is a non-receptor type tyrosine kinase, known to be overexpressed in various cancers including pancreatic cancer. The biological role of PTK6 in cancer remains unclear. We hypothesized that PTK6 is a key regulator of pancreatic cancer invasion.
Methods:
We used 3 cell lines derived from human pancreatic cancers, BxPC3, Panc1, and MIAPaCa2. PTK6 expression and activation were evaluated using western blotting. PTK6 expression was manipulated using siRNA gene silencing or transfection of expression vector. Cellular migration and invasion were evaluated using a Boyden chamber transmigration assay without or with Matrigel, respectively. Downstream signals associated with the effect of PTK6 on cellular migration and invasion were assayed using western blotting and a specific small molecule inhibitor.
Results:
Pancreatic cancer cell lines expressed PTK6 at various levels; BXPC3 expressed PTK6 robustly, while Panc1 and MIAPaCa2 expressed much lower levels of PTK6. In all 3 cell lines, suppression of PTK6 expression by siRNA significantly reducted both cellular motility and invasion through matrigel (0.59/0.49 fold for BXPC3, 0.61/0.62 for Panc1, 0.42/0.39 for MIAPaCa2, respectively, p<0.05 for each). In contrast, forced over-expression of PTK6 by transfection of a PTK6 expression vector in Panc1 and MIAPaCa2 cells significantly increased cellular migration and invasion (1.57/1.67 fold for Panc1, and 1.44/1.57 for MIAPaCa2, respectively, p< 0.05). Gene silencing of PTK6 reduced the activation of ERK1/2, but not AKT and STAT3, while overexpression of PTK6 increased ERK1/2 activation. When the cells were treated with U0126, a specific inhibitor of ERK1/2, the effect of PTK6 overexpression on cellular migration/invasion was completely abolished.
Conclusion:
PTK6 regulates cellular migration and invasion in pancreatic cancer, via the MAPK/ERK signaling pathway. Our findings suggest that PTK6 may be a novel therapeutic target for pancreatic cancer.