The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis

Siegfried, Géraldine; Basak, Ajoy; Cromlish, James A.; Benjannet, Suzanne; Marcinkiewicz, Jadwiga; Chrétien, Michel; Seidah, Nabil G.; Khatib, Abdel‐Majid

doi:10.1172/jci17220

Cited by 99 publications

(90 citation statements)

References 40 publications

(68 reference statements)

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“…These lymphangiogenic growth factors include VEGF-A, VEGF-C, VEGF-D, PDGF, HGF, Ang-1, Ang-2, IGF-1/2 and FGF-2 (bFGF) (18). Of them, most important lymphangiogenic growth factors are VEGF-C, VEGF-D and their cognate receptor VEGFR-3 located on lymphatic endothelial cells (6)(7)(8)(9)(10)(18)(19)(20)(21). These molecules play an important role on lymphangiogenesis and distinguish subtypes in tumor metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor-associated lymphatic vessels, also referred to as tumor lymphangiogenesis (2), i.e., new lymphatic vessel formation in cancer (3), act as a conduit by which disseminating tumor cells access regional lymph nodes and form metastases (4,5). Lymphangiogenic growth factors, which include the secreted glycoproteins vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor-D (VEGF-D) and their cognate receptor tyrosine kinase vascular endothelial growth factor receptor-3 (VEGFR-3) located on lymphatic endothelial cells can advance or regulate proliferation, migration, metastasis and survival of lymphatic endothelial cells (LECs), and lymphatic tube formation in physiological and pathological conditions such as wound repair, tissue regeneration and tumorigenesis (6)(7)(8). These molecules play an important role on lymphangiogenesis and metastatic spread of tumor cells to lymph nodes (9,10).…”

Section: Introductionmentioning

confidence: 99%

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Suppression of lymphangiogenesis in human lymphatic endothelial cells by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 with norcantharidin

Liu¹,

Qiu²,

Yuan³

et al. 2012

International Journal of Oncology

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Lymph node metastasis of tumors is a crucial early step in the metastatic process. Tumor lymphangiogenesis plays an important role in promoting tumor metastasis to regional lymph nodes. Norcantharidin (NCTD) has been reported to possess potent anti-angiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor-associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we investigated the effect of NCTD on proliferation, apoptosis, migration, invasion and the lymphatic tube formation, lymphangiogenesis, of human lymphatic endothelial cells (HLECs) in vitro by MTT, proliferation assay, Hoechst staining and flow cytometry, scraping line method, Matrigel invasion assay, inverted or fluorescence microscope and transmission electron microscope. Moreover, the underlying mechanisms, such as VEGF-C, VEGF-D, VEGFR-3 at protein and mRNA levels in lymphangiogenesis using 3-dimensional (3-D) culture of HLECs were measured by immunohistochemistry, western blotting and real-time polymerase chain reaction (RT-PCR). It was shown that NCTD inhibited proliferation, migration, invasion and lymphatic tube formation (forming-lymphatic and/or formed-lymphatic) of HLECs, induced HLEC apoptosis (all P<0.01) significantly, in a dose- and time-dependent manner (IC50 6.8 µg/ml); and downregulated the expression of VEGF-C, VEGF-D and VEGFR-3 at protein or/and mRNA levels (P<0.01) in HLEC lymphatic tube formation. Thus, we identified for the first time that NCTD inhibited HLEC lymphangiogenesis by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 in vitro. The present findings may be of importance to explore the therapeutical target or strategy of NCTD for tumor lymphangiogenesis and lymphatic metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Suppression of lymphangiogenesis in human lymphatic endothelial cells by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 with norcantharidin

Liu¹,

Qiu²,

Yuan³

et al. 2012

International Journal of Oncology

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“…In some experiments cDNA of human hepcidin was inserted into the pIRES2-EGFP vector containing a C-terminal V5 epitope, allowing protein detection with a V5 monoclonal antibody (Invitrogen) 19 20. Using the QuickChange site-directed mutagenesis kit (Stratagene, La Jolla, California, USA) and the human hepcidin primers 5′-CCCATGTTCCAGAGCTCATCCTCGAGTGACACCCAG-3′ and 5′-TGAGCTCTGCAACATGGGCATCCAGCTGGC-3′ the hepcidin mutant (FQRRRRR 59 DT into FQSSSSS 59 DT) was generated by PCR.…”

Section: Methodsmentioning

confidence: 99%

“…Using Trizol reagent (Invitrogen), total RNA was extracted and RT-PCR analysis were performed as described in detail elsewhere19 20 using the primers indicated in table 1. Amplified PCR products were analysed on a 2% agarose gel.…”

Section: Methodsmentioning

confidence: 99%

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Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7

Scamuffa

Basak²,

Lalou

et al. 2008

Gut

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Deficiency screen identifies a novel role for beta 2 tubulin in salivary gland and myoblast migration in the Drosophila embryo

Jattani

Patel

Kerman

et al. 2009

Developmental Dynamics

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The Drosophila embryonic salivary gland is an epithelial organ formed by the coordinated invagination and migration of primordial cells. To identify genes that regulate gland migration we performed a deficiency screen of the third chromosome. Here, we report on the analysis of the beta 2 tubulin isoform (β2t) that maps at 85D15. We show that in β2t mutant embryos, salivary glands did not complete their posterior migration and that migration of fusion competent myoblasts (FCMs) and longitudinal visceral muscle founder (LVMF) cells between the gland and CVM was delayed. We also demonstrate that gland migration defects correlate with reduced βPS and αPS2 integrin expression in the surrounding mesoderm and that β2t genetically interacts with genes encoding integrin αPS1 and αPS2 subunits. Our studies reveal for the first time that β2t is expressed in embryogenesis and that β2t plays an important role in salivary gland and myoblast migration, possibly through proper regulation of integrin adhesion proteins.

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The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis

Cited by 99 publications

References 40 publications

Suppression of lymphangiogenesis in human lymphatic endothelial cells by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 with norcantharidin

Suppression of lymphangiogenesis in human lymphatic endothelial cells by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 with norcantharidin

Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7

Deficiency screen identifies a novel role for beta 2 tubulin in salivary gland and myoblast migration in the Drosophila embryo

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