Abstract
Pancreatic cancer remains one of the most deadly cancers with a grave prognosis. Despite continuous efforts to improve remedial values, limited progress has been made. We have reported that dual specificity phosphatase 28 (DUSP28) has a critical role of chemo-resistance and migration in pancreatic cancers. However, its mechanism remains unclear. Here, we further clarify the function of DUSP28 in pancreatic cancers. Analysis using a public microarray database and in vitro assay indicated a critical role of platelet derived growth factor A (PDGF-A) in pancreatic cancer malignancy. PDGF-A was positively regulated by DUSP28 expression at the mRNA and protein levels. Enhanced DUSP28 sensitized pancreatic cancer cells to exogenous PDGF-A treatment in migration, invasion, and proliferation. Transfection with siRNA targeting DUSP28 blunted the influence of administered PDGF-A by inhibition of phosphorylation of FAK, ERK1/2, and p38 signalling pathways. In addition, DUSP28 and PDGF-A formed an acquired autonomous autocrine-signaling pathway. Furthermore, targeting DUSP28 inhibited the tumor growth and migratory features through the blockade of PDGF-A expression and intracellular signaling in vivo. Our results establish novel insight into DUSP28 and PDGF-A related autonomous signaling pathway in pancreatic cancer.
Highlights
Pancreatic cancer is one of the most lethal malignancies with a 5-year survival rate
Viability was measured by the WST-1 assay (n = 3; Tukey’s post hoc test was applied to detect differences in ANOVA, p < 0.0001; asterisks indicate a significant difference compared with 0% inhibition, *p < 0.05, **p < 0.01, n.s., non-significant) (D) Three human pancreatic cancer cell lines were incubated with 50 μg/L Platelet-derived growth factor-A (PDGF-A) for 6 h
We previously demonstrated that dual specificity phosphatase 28 (DUSP28) has a functional role in drug resistance and migratory activity, and tunes the expression of pivotal molecules including MUC5B and MUC16 in human pancreatic cancers[15,25]
Summary
Pancreatic cancer is one of the most lethal malignancies with a 5-year survival rate
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