Journal
NEOPLASIA
Volume 8, Issue 9, Pages 733-746Publisher
ELSEVIER SCIENCE INC
DOI: 10.1593/neo.06274
Keywords
oral cancer; IL-6; cytokine; gene expression regulation; transcription factor
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The development of head and neck squamous cell carcinoma (HNSCC) involves the accumulation of genetic and epigenetic alterations in tumor-suppressor proteins, together with the persistent activation of growth-promoting signaling pathways. The activation of epidermal growth factor receptor (EGFR) is a frequent event in HNSCC. However, EGFR-independent mechanisms also contribute to the activation of key intracellular signaling routes, including signal transducer and activator of transcription- 3 (STAT3), nuclear factor kappa B (NF kappa B), and Akt. Indeed, the autocrine activation of the gp130 cytokine receptor in HNSCC cells by tumor-released cytokines, such as IL-6, can result in the EGFR-independent activation of STAT3. In this study, we explored the nature of the molecular mechanism underlying enhanced IL-6 secretion in HNSCC cells. We found that HNSCC cells display an increased activity of the IL-6 promoter, which is dependent on the presence of an intact NF kappa B site. Furthermore, NF kappa B inhibition downregulated IL-6 gene and protein expression, and decreased the release of multiple cytokines. Interestingly, interfering with NF kappa B function also prevented the autocrine/paracrine activation of STAT3 in HNSCC cells. These findings demonstrate a cross-talk between the NF kappa B and the STAT3 signaling systems, and support the emerging notion that HNSCC results from the aberrant activity of a signaling network.
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