Abstract

Angiogenesis is essential for tumor progression, MEN1 gene encodes the menin protein, which is known as a tumor suppressor in lung tissue. Our previous study have shown that vascular density is significantly increased in menin‐deficient lung cancer, suggesting that menin deficiency may promote the malignant progression of lung cancer by enhancing angiogenesis. However, whether menin play an important role in angiogenesis of lung cancer and the underlying mechanisms remain unclear. In this study, lung‐specific Kras G12D mutation induced mouse lung cancer model, clinical human lung cancer tissues, lung cancer and vascular endothelial cell lines were utilized, RNA‐seq, ATAC‐seq, ChIP, tube formation, sprouting, invasion and migration experiments were applied to investigate the role and mechanism of MEN1 in lung cancer angiogenesis. The result show menin were negatively related to angiogenesis markers and phenotype. Menin deficiency indirectly upregulates MMP10 transcription through activation of the transcription factor JunD. The expression of MMP10 further activates the EGFR receptor in vascular endothelial cells, thereby initiating the AKT/ERK signaling pathway. Inhibition MMP10 reversed menin low expression induce angiogenic phenotype and tumor progress. In conclusion, menin deficiency promotes angiogenesis through upregulates MMP10, targeting MMP10 with inhibitor represent an effective anti‐angiogenic strategy for treating MEN1 ‐deficient lung cancer. MEN1 deficiency promotes JunD‐mediated upregulation of MMP10 expression, which cleaves pro‐HB‐EGF and activates endothelial EGFR. This triggers the PI3K/Akt and MEK/ERK signaling pathways, thereby driving angiogenesis and tumor progression. MMP10 inhibitor treatment blocks this cleavage, suppresses EGFR signaling, and thereby delays malignant progression.