Cigarette Smoke Induces Angiogenic Activation in the Cancer Field Through Dysregulation of an Endothelial microRNA

Authors

Asawari Korde
Anuradha Ramaswamy
Seth Anderson
Lei Jin
Jian-Ge Zhang
Buqu Hu
Walter V Velasco
Lixia Diao
Jing Wang
Margaret A Pisani
Maor Sauler
Daniel J Boffa
Jonathan T Puchalski
Xiting Yan
Seyed Javad Moghaddam
Shervin S Takyar

Publication Date

3-28-2025

Journal

Communications Biology

Abstract

Cigarette smoke (CS) creates a "cancer field" in the lung that promotes malignant transformation. The molecular changes within this field are not fully characterized. We examined the significance of microRNA-1 (miR-1) downregulation as one of these changes. We found that tumor miR-1 levels in three non-small cell lung cancer cohorts show inverse correlations with the smoking burden. Lung MiR-1 levels follow a spatial gradient, have prognostic significance, and correlate inversely with the molecular markers of injury. In CS-exposed lungs, miR-1 is specifically downregulated in the endothelium. Exposure to CS induces angiogenesis by selectively degrading mature miR-1 via a vascular endothelial growth factor-driven pathway. Applying a multi-step molecular screen, we identified angiogenic genes regulated by miR-1 in the lungs of smokers. Knockdown of one of these genes, Notch homolog protein 3, simulates the anti-angiogenic effects of miR-1. These findings suggest that miR-1 can be used as an indicator of malignant transformation.

Keywords

MicroRNAs, Humans, Lung Neoplasms, Neovascularization, Pathologic, Gene Expression Regulation, Neoplastic, Carcinoma, Non-Small-Cell Lung, Female, Cigarette Smoking, Male

DOI

10.1038/s42003-025-07710-y

PMID

40155749

PMCID

PMC11953391

PubMedCentral® Posted Date

3-28-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes