Cigarette smoke induces angiogenic activation in the cancer field through dysregulation of an endothelial microRNA
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.
Authors
- Daniel J. Boffa (ORCID: https://orcid.org/0000-0001-5471-8833)
- Maor Sauler (ORCID: https://orcid.org/0000-0001-5240-7978)
- Seyed Javad Moghaddam (ORCID: https://orcid.org/0000-0002-5350-307X)
- Jiange Zhang (ORCID: https://orcid.org/0000-0002-1434-6040)
- Anuradha Ramaswamy
- Buqu Hu (ORCID: https://orcid.org/0000-0001-7233-987X)
- Walter V. Velasco (ORCID: https://orcid.org/0000-0001-9101-5758)
- Jonathan Puchalski (ORCID: https://orcid.org/0000-0002-6538-5541)
- Seth Anderson (ORCID: https://orcid.org/0000-0003-2419-0585)
- Xiting Yan (ORCID: https://orcid.org/0000-0001-8688-9004)
- S. Takyar (ORCID: https://orcid.org/0000-0003-1369-1544)
- Margaret A. Pisani (ORCID: https://orcid.org/0000-0001-8601-7038)
- Lixia Diao (ORCID: https://orcid.org/0000-0001-6995-4492)
- Lei Jin (ORCID: https://orcid.org/0000-0002-4369-7325)
- Jing Wang (ORCID: https://orcid.org/0000-0002-5398-0802)
- Asawari Korde
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Yale University (US)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-03-28
- DOI
- https://doi.org/10.1038/s42003-025-07710-y
- Citations
- 4
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 3.75
Funders
- U.S. Department of Defense
- National Heart, Lung, and Blood Institute
- National Cancer Institute