RNAi-mediated silencing of VEGF-C inhibits non-small cell lung cancer progression by simultaneously down-regulating the CXCR4, CCR7, VEGFR-2 and VEGFR-3-dependent axes-induced ERK, p38 and AKT signalling pathways.

Abstract

Vascular endothelial growth factor C (VEGF-C) expression is associated with the malignant tumour phenotype making it an attractive therapeutic target. We investigated the biological roles of VEGF-C in tumour growth, migration, invasion and explored the possibility of VEGF-C as a potential therapeutic target for the treatment of non-small cell lung cancer (NSCLC). A lentivirus-mediated RNA interference (RNAi) technology was used to specifically knockdown the expression of VEGF-C in A549 cells. Quantitative reverse transcriptase-polymerase chain reaction, flow cytometry, Western blot, immunohistochemistry, cellular growth, migration, invasion and ELISA assays were used to characterise VEGF-C expression in vitro. A lung cancer xenograft model in nude mice was established to investigate whether knockdown of VEGF-C reduced tumour growth in vivo. Silencing of VEGF-C suppressed tumour cell growth, migration and invasion in vitro; suppressed tumour growth, angiogenesis and lymphangiogenesis by tail vein injection of lentivirus encoded shRNA against VEGF-C in vivo. More importantly, silencing of VEGF-C also trapped the VEGFR-2, VEGFR-3, CXCR4, CCR7-dependent axes, and down-regulated the AKT, ERK and p38 signalling pathways. These results suggest that VEGF-C has a multifaceted role in NSCLC growth, migration and invasion; that VEGF-C-mediated autocrine loops with their cognate receptors and chemokine receptors are significant factors affecting tumour progression; and that RNAi-mediated silencing of VEGF-C represents a powerful therapeutic approach for controlling NSCLC growth and metastasis.

• Authors: Yukuan Feng, Jing Hu, Jing Ma, Kejian Feng, Xiaoli Zhang, Shucai Yang, Wei Wang, Jianguo Zhang, Yafang Zhang
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 47 Issue 15 Pg. 2353-63 (Oct 2011) ISSN: 1879-0852 [Electronic] England
• PMID: 21680174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• CCR7 protein, human
• CXCR4 protein, human
• Receptors, CCR7
• Receptors, CXCR4
• VEGFC protein, human
• Vascular Endothelial Growth Factor C
• Vascular Endothelial Growth Factor Receptor-2
• Vascular Endothelial Growth Factor Receptor-3
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Base Sequence
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (blood supply, enzymology, genetics, pathology, therapy)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Down-Regulation
• Enzyme-Linked Immunosorbent Assay
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Flow Cytometry
• Genotype
• Humans
• Immunohistochemistry
• Lung Neoplasms (blood supply, enzymology, genetics, pathology, therapy)
• Lymphangiogenesis
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Sequence Data
• Neoplasm Invasiveness
• Neovascularization, Pathologic (enzymology, prevention & control)
• Phenotype
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• Receptors, CCR7 (metabolism)
• Receptors, CXCR4 (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Time Factors
• Transfection
• Tumor Burden
• Vascular Endothelial Growth Factor C (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Vascular Endothelial Growth Factor Receptor-3 (metabolism)
• Xenograft Model Antitumor Assays
• p38 Mitogen-Activated Protein Kinases (metabolism)