PrP(C) Glycoprotein Modulates Atmospherically Relevant Artificial Particulate Matter-Induced Development of Lung Cancer in Mice.

Fine particulate matter with a diameter less than 2.5 μm (PM(2.5)) is an environmental risk factor for lung cancer. However, the molecular mechanisms linking PM(2.5) exposure to tumorigenesis remain unclear. We identified the cellular prion protein (PrP(C)) as a critical regulator of susceptibility to PM(2.5)-induced lung pathologies. PrP(C) and Sirt1 expression levels were lower, whereas HIF-1α expression was higher, in aged compared to younger C57BL/6 mice, which correlated with increased mortality and lung cancer susceptibility following PM(2.5) exposure. Prnp mice (PrP(C) wild-type (WT) and knockout (KO) mice) were exposed to PM(2.5) at 50 μg/m(3) for 2 h per day over 5 days. Two PM(2.5) sources were used: a synthetic ion-organic acid mixture and an urban standard (NIST 1648a), which are rich in heavy metals and polycyclic aromatic hydrocarbons. Lung pathology was evaluated by using imaging, histology, immunohistochemistry, and Western blotting. PrP(C) deficiency recapitulated and exacerbated age-associated pathology, promoting emphysema, hypoxia, angiogenesis, and tumorigenesis via dysregulating the Sirt1-p53-HIF1α axis. NIST triggered more aggressive tumorigenesis than the synthetic mixture, underscoring the role of particle composition. PM(2.5) has environmental and public health impacts, particularly in older adults, and PrP(C) is a mechanistic regulator and potential biomarker of pollution-associated lung cancer.