title: Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-κB pathways in the oral squamous cell carcinoma microenvironment.
abstract: Hypoxia is a prominent feature of the microenvironment of solid tumors and may contribute to tumor progression through the oxygen-sensitive transcriptional regulator hypoxia-inducible factor-1 (HIF-1). Chronic inflammation is another typical feature. Inflammatory mediators, including Toll-like receptors (TLRs) and nuclear factor-κB (NF-κB), play an important role in cancer development. Recent studies have revealed extensive cross-talk between hypoxia and inflammation signaling, though the mechanisms remain unclear. Our results confirm that TLR3 and TLR4 are highly expressed in oral squamous cell carcinoma (OSCC). Activation of TLR3 and TLR4 stimulated the expression of HIF-1 through NF-κB. In addition, HIF-1 increased the expression of TLR3 and TLR4 through direct promoter binding. Thus, the TLR/NF-κB pathway forms a positive feedback loop with HIF-1. These results indicate a novel cross-talk between the TLR/NF-κB and HIF-1 signaling, which may contribute to OSCC initiation and progression. With the elucidation of this novel mechanism, it might serve as a basis for future microenvironment targeted cancer therapy.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.|Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
authors.forename: Shengwei
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.|Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
authors.forename: Wenguang
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.|Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.|Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.|Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.|Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.|Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
authors.forename: Qingang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.|Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000737:chemistry; D009062:Mouth Neoplasms / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011070:Poly I-C / Q000737:chemistry; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011070:Poly I-C
keywords: HIF-1; NF-κB; TLR; oral squamous cell carcinoma; tumor microenvironment