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April 7, 2026Journal of Cancer0 citationsOpen Access

WISP-3 promotes angiogenesis in non-small cell lung cancer through p38/JNK-c-Jun-mediated PDGF-A upregulation

ECEn-Ming ChangMemorial Hospital SLSyuan-Ling LinChina Medical University CCChing-Yuan Cheng

Key Points

To explore how WISP-3 influences angiogenesis in non-small cell lung cancer through specific signaling pathways.
Used human lung adenocarcinoma cells treated with recombinant WISP-3 to analyze tube formation in endothelial cells.
Measured PDGF-A expression levels at mRNA and protein levels in NSCLC cell lines.
Utilized siRNA to knockdown PDGF-A and assess its role in tube formation.
Investigated p38 and JNK signaling pathway activation through phosphorylation.
Applied pharmacological inhibitors of p38, JNK, and c-Jun to assess their effects on angiogenesis.
Conditioned medium from WISP-3 treated cells increased tube formation in HUVECs in a dose-dependent manner.
WISP-3 upregulated PDGF-A expression, whereas other angiogenic factors remained unchanged.
Knockdown of PDGF-A significantly reduced WISP-3-induced tube formation in HUVECs.
Inhibition of p38, JNK, or c-Jun diminished angiogenesis and PDGF-A expression.

Abstract

Angiogenesis is a pivotal process for tumor progression and metastasis in non-small cell lung cancer (NSCLC).However, the molecular mechanisms by which WNT1-inducible signaling pathway protein 3 (WISP-3) contributes to NSCLC angiogenesis remain poorly defined.This study investigated the role of WISP-3 in regulating pro-angiogenic signaling in lung adenocarcinoma (LUAD) cells.Conditioned medium from H1299 and A549 cells treated with recombinant WISP-3 (0-100 ng/mL) significantly and dose-dependently enhanced the tube formation of human umbilical vein endothelial cells (HUVECs).WISP-3 selectively upregulated platelet-derived growth factor A (PDGF-A) expression at both mRNA and protein levels in NSCLC cell lines, while other angiogenic factors remained unaffected.Notably, knockdown of PDGF-A using siRNA markedly abolished WISP-3-induced HUVEC tube formation, confirming PDGF-A as a critical mediator in this process.Mechanistically, WISP-3 rapidly triggered the phosphorylation of p38 and JNK signaling pathways.These activations led to the phosphorylation of the transcription factor c-Jun, which in turn promoted PDGF-A gene expression.Pharmacological inhibition of p38 (Adezmapimod), JNK (SP600125), or c-Jun (T-5224) effectively suppressed WISP-3-induced c-Jun activation, PDGF-A expression, and subsequent angiogenesis.Collectively, our findings identify a novel WISP-3/p38-JNK/c-Jun/PDGF-A signaling axis that drives vascular remodeling in NSCLC.Targeting WISP-3 or its downstream effectors may represent a promising therapeutic strategy for anti-angiogenic treatment in lung cancer.

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