HIF-α/MIF and NF-κB/IL-6 axes contribute to the recruitment of CD11b+Gr-1+ myeloid cells in hypoxic microenvironment of HNSCC.
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.
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.
Guiquan
G
Zhu
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Yaling
Y
Tang
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Ning
N
Geng
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Min
M
Zheng
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Jian
J
Jiang
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.
Ling
L
Li
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Kaide
K
Li
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Zhengge
Z
Lei
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Wei
W
Chen
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Yunlong
Y
Fan
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Xiangrui
X
Ma
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Longjiang
L
Li
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, PR China.
Xiaoyi
X
Wang
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.
Xinhua
X
Liang
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002633:Chemotaxis; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D008819:Mice, Nude; D022423:Myeloid Cells / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment
D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508600:IL6 protein, human; D015850:Interleukin-6; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D019707:Receptors, Chemokine; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human