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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2022

Open Access 01-12-2022 | Research

Suppression of VEGFD expression by S-nitrosylation promotes the development of lung adenocarcinoma

Authors: Qiangqiang He, Meiyu Qu, Tingyu Shen, Yana Xu, Jiahao Luo, Dan Tan, Chengyun Xu, Muhammad Qasim Barkat, Ling-Hui Zeng, Ximei Wu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2022

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Abstract

Background

Vascular endothelial growth factor D (VEGFD), a member of the VEGF family, is implicated in angiogenesis and lymphangiogenesis, and is deemed to be expressed at a low level in cancers. S-nitrosylation, a NO (nitric oxide)-mediated post-translational modification has a critical role in angiogenesis. Here, we attempt to dissect the role and underlying mechanism of S-nitrosylation-mediated VEGFD suppression in lung adenocarcinoma (LUAD).

Methods

Messenger RNA and protein expression of VEGFD in LUAD were analyzed by TCGA and CPTAC database, respectively, and Assistant for Clinical Bioinformatics was performed for complex analysis. Mouse models with urethane (Ure)–induced LUAD or LUAD xenograft were established to investigate the role of S-nitrosylation in VEGFD expression and of VEGFD mutants in the oncogenesis of LUAD. Molecular, cellular, and biochemical approaches were applied to explore the underlying mechanism of S-nitrosylation-mediated VEGFD suppression. Tube formation and wound healing assays were used to examine the role of VEGFD on the angiogenesis and migration of LUAD cells, and the molecular modeling was applied to predict the protein stability of VEGFD mutant.

Results

VEGFD mRNA and protein levels were decreased to a different extent in multiple primary malignancies, especially in LUAD. Low VEGFD protein expression was closely related to the oncogenesis of LUAD and resultant from excessive NO-induced VEGFD S-nitrosylation at Cys277. Moreover, inhibition of S-nitrosoglutathione reductase consistently decreased the VEGFD denitrosylation at Cys277 and consequently promoted angiogenesis of LUAD. Finally, the VEGFDC277S mutant decreased the secretion of mature VEGFD by attenuating the PC7-dependent proteolysis and VEGFDC277S mutant thus reversed the effect of VEGFD on angiogenesis of LUAD.

Conclusion

Low-expression of VEGFD positively correlates with LUAD development. Aberrant S-nitrosylation of VEGFD negates itself to induce the tumorigenesis of LUAD, whereas normal S-nitrosylation of VEGFD is indispensable for its secretion and repression of angiogenesis of LUAD.
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Metadata
Title
Suppression of VEGFD expression by S-nitrosylation promotes the development of lung adenocarcinoma
Authors
Qiangqiang He
Meiyu Qu
Tingyu Shen
Yana Xu
Jiahao Luo
Dan Tan
Chengyun Xu
Muhammad Qasim Barkat
Ling-Hui Zeng
Ximei Wu
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2022
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-022-02453-8

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