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<p>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.</p>

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Cigarette smoke induces angiogenic activation in the cancer field through dysregulation of an endothelial microRNA

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月28日

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  • 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

摘要

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.