Dataset Information

Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway.

ABSTRACT: Signaling through vascular endothelial growth factor C (VEGF–C) and VEGF receptor 3 (VEGFR-3) plays a central role in lymphangiogenesis and the metastasis of several cancers via the lymphatics. Recently, the Slit2/Robo4 pathway has been recognized as a modulator of vascular permeability and integrity. Signaling via the Robo receptor inhibits VEGF-mediated effects; however, its effects on lymphatic endothelial cell function have not been well characterized.We found that pretreatment with Slit2N, an active fragment of Slit2, inhibited VEGF-C-mediated lung-derived lymphatic endothelial cell (L-LEC) proliferation, migration, and in vitro tube formation. Slit2N induced the internalization of VEGFR-3, which blocked its activation, and inhibited the activation of the PI3K/Akt pathway by VEGF-C in L-LECs. Moreover, we found that inhibition of VEGF-C-induced effects by Slit2N was Robo4-dependent.These results indicate that Slit2N/Robo4 modulates several key cellular functions, which contribute to lymphangiogenesis, and identify this ligand-receptor pair as a potential therapeutic target to inhibit lymphatic metastasis of VEGF-C-overexpressing cancers and manage lymphatic dysfunctions characterized by VEGF-C/VEGFR-3 activation.

SUBMITTER: Yu J

PROVIDER: S-EPMC4122147 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway.

Yu Jinlong J Zhang Xuefeng X Kuzontkoski Paula M PM Jiang Shuxian S Zhu Weiquan W Li Dean Y DY Groopman Jerome E JE

Cell communication and signaling : CCS 20140407

<h4>Background</h4>Signaling through vascular endothelial growth factor C (VEGF–C) and VEGF receptor 3 (VEGFR-3) plays a central role in lymphangiogenesis and the metastasis of several cancers via the lymphatics. Recently, the Slit2/Robo4 pathway has been recognized as a modulator of vascular permeability and integrity. Signaling via the Robo receptor inhibits VEGF-mediated effects; however, its effects on lymphatic endothelial cell function have not been well characterized.<h4>Results</h4>We fo ...[more]

PMID: 24708522

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Project description:The aim of the present study was to explore the effects of BRAF-activated non-protein coding RNA (BANCR) on pancreatic microlymphangiogenesis in pancreatic cancer (PC) and its molecular mechanism under hypoxic conditions. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the expression of BANCR in SW1990 and PANC-1 PC cell lines under normoxic and hypoxic conditions. Subsequently, the expression of BANCR in the PC cells was knocked down using small interfering RNAs (siRNAs). Western blotting and RT-qPCR analyses were performed to detect the expression of hypoxia-inducible factor (HIF-1α), VEGF-C and VEGFR-3 in the transfected cells. In addition, the transfected PC cells were co-cultured with human lymphatic endothelial cells and the lymphatic microvessel density (MLVD) was detected under normal and hypoxic conditions. Furthermore, HIF-1α expression in the PC cells was knocked down using siRNAs, and VEGF-C and VEGFR-3 mRNA expression in the HIF-1α knockdown cells was detected using RT-qPCR. The results showed that the expression of BANCR in the SW1990 and PANC-1 PC cell lines was significantly higher than that in human pancreatic duct endothelial cells. Additionally, the expression of BANCR was significantly increased in PC cells under hypoxic conditions compared with normoxic conditions. The MLVD of PC cells under hypoxic conditions was significantly higher compared with that under normoxic conditions, and the MLVD in the si-BANCR group was lower than that in the si-NC group, indicating that si-BANCR downregulated MLVD. These results indicate that BANCR positively regulated the expression of HIF-1α in PC cells at the transcriptional and translational levels. Finally, the expression levels of VEGF-C and VEGFR-3 in PC cells were significantly reduced when BANCR or HIF-1α expression was knocked down. In conclusion, the results demonstrate that the expression of BANCR in PC cells was significantly increased under hypoxic conditions and suggest that BANCR promoted tumor cell lymphangiogenesis by upregulating the HIF-1α/VEGF-C/VEGFR-3 pathway, which plays an important role in the process of PC lymph node metastasis.

Dataset Information

Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway.

Publications

Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway.

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