Abstract
IntroductionThe rising incidence and extremely poor prognosis makes pancreatic adenocarcinoma (PDAC) becoming one of the most malignant cancers. Dissemination through the lymphatic/vascular system is a critical process causing poor prognosis; however, how this process is regulated remains largely unknown. We aimed to elucidate the novel function of the tumour suppressor dual specificity phosphatase-2 (DUSP2), the master negative regulator of MAPK signalling, in PDAC progression and the mechanism by which DUSP2 mediates lymphovascular invasion (LVI).Material and methodsDUSP2 expression was examined in human pancreatic tumours. Orthotopic pancreatic tumour mouse models were used to determine the gain and loss of DUSP2 in PDAC progression. RT-qPCR and Western blotting were used to measure the expression of VEGF-C regulated by DUSP2. The autocrine and paracrine effects of DUSP2/VEGF-C axis were measured by migration/invasion assays. Proprotein convertase activity assay was performed to investigate the regulation of VEGF-C. Extracellular vesicle (EV) secretion was measured by nanoparticle tracking analysis, confocal imaging and Western blotting.Results and discussionsDUSP2 knockdown (KD) tumours developed increased lymphangiogenesis and increased LVI in mouse model of pancreatic cancer. Forced expression of DUSP2 abolished pancreatic cancer development. A significant increase in the functional form of VEGF-C of DUSP2-KD pancreatic cancer cells promoted survival and migration of lymphatic endothelial cells in a VEGFR dependent manner. In addition, VEGF-C signalling mediated migration/invasion ability of DUSP2-KD pancreatic cancer cells. Knockdown of DUSP2 not only increased VEGFC mRNA level but also enhanced the conversion of proform VEGF-C to become the mature form, which is associated with increased activity of proprotein convertase. Loss-of-DUSP2 enhanced EV secretion thus promoted the release of mature form VEGF-C. Novel histone deacetylase inhibitor, exerting similar effect as DUSP2 re-expression, can not only diminish VEGF-C secretion but also confer synergistic effect with routinely used chemotherapeutic drug for PDAC.ConclusionWe provide new evidence demonstrating that loss of DUSP2 in pancreatic cancer cells increases expression of VEGF-C, which exerts autocrine and paracrine functions to promote early dissemination of pancreatic cancer.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have