Regulation of Pancreatic Cancer Dissemination by Dual Specificity Phosphatase-2 / VEGF-C Signaling

摘要

Pancreatic ductal adenocarcinoma (PDAC) remains as one of the most malignant cancers with less than 5% 5-year survival rate The low survival rate is due at least in part to late diagnosis since most PDAC patients were first diagnosed after the tumor has disseminated Lymphatic vessels are the most common route for solid tumor cells to spread therefore the increased expression of lymphangiogenic growth factors may play a critical role in PDAC metastasis Our previous study found dual specificity phosphatase 2 (DUSP2) a critical tumor suppressor gene in controlling multiple cancer malignancy is markedly decreased in many cancers We herein further investigate the pathological consequence of DUSP2 downregulation in PDAC metastasis To dissect the underlying mechanism we performed microarray analysis and the data indicated one critical lymphangiogenic factor vascular endothelial growth factor C (VEGF-C) is negatively regulated by DUSP2 We hypothesized that downregulation of DUSP2 in PDAC cells promotes tumor cell migration and metastasis by up?regulation of VEGF?C Knockdown of DUSP2 increased VEGF-C expression while overexpression of DUSP2 decreased VEGF-C in PDAC cells As a growth factor VEGF-C has to be cleaved and secreted to extracellular space to be functional We demonstrated that loss-of-DUSP2 not only stimulates VEGF-C transcription but also regulates VEGF-C cleavage at the post-translational level as evidenced by that loss-of-DUSP2-enhanced VEGF-C secretion was diminished by addition of proprotein convertase inhibitor To test whether loss-of-DUSP-induced VEGF-C promotes lymphangiogenesis conditioned media from DUSP2 knockdown cells were used to treat lymphatic endothelial cells (LECs) As expected the conditioned media with elevated expression of VEGF-C promoted migration and growth of LECs and in vivo animal study also demonstrated that DUSP2 knockdown tumors developed more lymphatic vessels strongly suggesting that inhibition of DUSP2 promotes lymphangiogenesis via up-regulation of VEGF-C In addition to the paracrine effect on LECs we found that VEGF-C promotes cancer cells migration via an autocrine mechanism Knockdown of VEGF-C in PDAC cells significantly decreased cell invasion whilst enhanced invasion ability by DUSP2 knockdown can be abolished by treatment with VEGFR2/VEGFR3 inhibitor lenvatinib Thus loss-of-DUSP2-mediated VEGF-C upregulation can induce lymphatic vessel infiltration to the cancer tissue and at the same time increase pancreatic cancer cell migration to promote cancer cell dissemination Taken all together our results indicate that downregulation of DUSP2 during pancreatic cancer progression may lead to increased VEGF-C expression which promotes cancer malignancy via paracrine (lymphangiogenesis) and autocrine (tumor cell migration) mechanisms Our findings suggest that targeting VEGF-C or restoration of DUSP2 simultaneously may serve as an attractive therapeutic approach to inhibit pancreatic cancer progression Alternatively inhibiting VEGF-C from being processed by convertase might be another promising approach to inhibit PDAC dissemination and cancer malignancy

獎項日期	2016 8月 2
原文	English
監督員	Shaw-Jenq Tsai (Supervisor)