Increased alveolar epithelial TRAF6 via autophagy-dependent TRIM37 degradation mediates particulate matter-induced lung metastasis

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Autophagy. 2021 Sep 15:1-19. doi: 10.1080/15548627.2021.1965421. Online ahead of print.


Epidemiological and clinical studies have shown that exposure to particulate matter (PM) is associated with an increased incidence of lung cancer and metastasis. However, the underlying mechanism remains unclear. Here, we demonstrated the central role of PM-induced neutrophil recruitment in promoting lung cancer metastasis. We found that reactive oxygen species (ROS)-mediated alveolar epithelial macroautophagy/autophagy was essential for initiating neutrophil chemotaxis and pre-metastatic niche formation in the lungs in response to PM exposure. During PM-induced autophagy, the E3 ubiquitin ligase TRIM37 was degraded and protected TRAF6 from proteasomal degradation in lung epithelial cells, which promoted the NFKB-dependent production of chemokines to recruit neutrophils. Importantly, ROS blockade, autophagy inhibition or TRAF6 knockdown abolished PM-induced neutrophil recruitment and lung metastasis enhancement. Our study indicates that host lung epithelial cells and neutrophils coordinate to promote cancer metastasis to the lungs in response to PM exposure and provides ideal therapeutic targets for metastatic progression.Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ATII: alveolar type II; Cho-Traf6 siRNA: 5′-cholesterol-Traf6 siRNA; EMT: epithelial-mesenchymal transition; HBE: human bronchial epithelial; HCQ: hydroxychloroquine; MAPK: mitogen-activated protein kinase; NAC: N-acetyl-L-cysteine; NFKB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NS: normal saline; PM: particulate matter; ROS: reactive oxygen species; TRAF6: TNF receptor-associated factor 6; TRIM37: tripartite motif-containing 37.

PMID:34524943 | DOI:10.1080/15548627.2021.1965421