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.
Highlights
Oral squamous cell carcinoma (OSCC) is one of the most common cancers of the head and neck region [1]
We demonstrated that upregulation of HIF-1α was directly correlated with activation of TLR3 and TLR4 through nuclear factor-κB (NF-κB) signaling
Our results suggested that hypoxia-inducible factor-1 (HIF-1) could directly regulate Toll-like receptors (TLRs)/NF-κB signaling in oral squamous cell carcinoma (OSCC) cells, suggesting the existence of a www.impactjournals.com/oncotarget positive feedback loop between HIF-1 and TLR/NF-κB signaling in OSCC cells (Figure 10)
Summary
Oral squamous cell carcinoma (OSCC) is one of the most common cancers of the head and neck region [1]. Many strategies for the development of new OSCC therapeutics have considered the role of the tumor microenvironment in cancer development and progression [4]. In solid tumors such as OSCC, hypoxia and chronic inflammation are two of the most prominent features of tumor progression [5]. The oxygen pressure within solid tumors is heterogeneous and can range from approximately 5% O2 in well-vascularized regions to 1% O2 (hypoxic conditions) near necrotic regions [7]. The HIF-1 dimer regulates the expression of more than 100 downstream genes that protect cells under hypoxic conditions [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
