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      HIF-α/MIF and NF-κB/IL-6 axes contribute to the recruitment of CD11b+Gr-1+ myeloid cells in hypoxic microenvironment of HNSCC.

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          Abstract

          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-1α (HIF-1α)- and HIF-2α-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-1α and HIF-2α in HNSCC cells decreased MIF level but failed to inhibit the CD11b+Gr-1+ myeloid cell migration, because HIF-1α/2α KD enhanced nuclear factor κB (NF-κB) activity that increased IL-6 secretion. Simultaneously blocking NF-κB and HIF-1α/HIF-2α had better inhibitory effect on CD11b+Gr-1+ myeloid cell recruitment in the hypoxic zone than individually silencing HIF-1α/2α or NF-κB. In conclusion, the interaction between HIF-α/MIF and NF-κB/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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          Author and article information

          Journal
          Neoplasia
          Neoplasia (New York, N.Y.)
          1476-5586
          1476-5586
          Feb 2014
          : 16
          : 2
          Affiliations
          [1 ] State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China; Department of Head and Neck Surgery, Sichuan Cancer Hospital and Institute, Chengdu, PR China.
          [2 ] State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
          [3 ] State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China. Electronic address: lxh88866@scu.edu.cn.
          Article
          S1476-5586(14)80016-X
          10.1593/neo.132034
          3978397
          24709424
          Copyright © 2014 Neoplasia Press, Inc. All rights reserved.

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