期刊
NEOPLASIA
卷 16, 期 2, 页码 168-+出版社
ELSEVIER SCIENCE INC
DOI: 10.1593/neo.132034
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资金
- National Natural Science Foundation of China [81072215, 81272961, 81302375, 81372891, 81361120399]
- Fundamental Research Funds of the Central Universities of China
- State Key Laboratory of Oral Diseases Special Funded Projects
CD11b+Gr-1+ myeloid cells have gained much attention due to their roles in tumor immunity suppression as well as promotion of angiogenesis, invasion, and metastases. However, the mechanisms by which CD11b+Gr-1+ myeloid cells recruit to the tumor site have not been well clarified. In the present study, we showed that hypoxia could stimulate the migration of CD11b+Gr-1+ myeloid cells through increased production of macrophage migration inhibitory factor (MIF) and interleukin-6 (IL-6) by head and neck squamous cell carcinoma (HNSCC) cells. Hypoxia-inducible factor-1 alpha (HIF-1 alpha)-and HIF-2 alpha-dependent MIF regulated chemotaxis, differentiation, and pro-angiogenic function of CD11b+Gr-1+ myeloid cells through binding to CD74/CXCR2, and CD74/CXCR4 complexes, and then activating p38/mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinases (PI3K)/AKT signaling pathways. Knockdown (KD) of HIF-1 alpha and HIF-2 alpha in HNSCC cells decreased MIF level but failed to inhibit the CD11b+Gr-1+ myeloid cell migration, because HIF-1 alpha/2 alpha KD enhanced nuclear factor kappa B (NF-kappa B) activity that increased IL-6 secretion. Simultaneously blocking NF-kappa B and HIF-1 alpha/HIF-2 alpha had better inhibitory effect on CD11b+Gr-1+ myeloid cell recruitment in the hypoxic zone than individually silencing HIF-1 alpha/2 alpha or NF-kappa B. In conclusion, the interaction between HIF-alpha/MIF and NF-kappa B/IL-6 axes plays an important role in the hypoxia-induced accumulation of CD11b+Gr-1+ myeloid cells and tumor growth in HNSCC.
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