Journal
ONCOGENE
Volume 39, Issue 15, Pages 3179-3194Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-020-1207-6
Keywords
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Funding
- National Natural Science Foundation of China [81620108022, 91129303, 91729302, 81572759, 81572693]
- Shenzhen Municipal Government of China [KQTD20170810160226082]
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Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE(2) signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE(2) signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE(2) signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE(2) signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE(2) signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.
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