Molecular cross-talk between the NFkappaB and STAT3 signaling pathways in head and neck squamous cell carcinoma

Neoplasia. 2006 Sep;8(9):733-46. doi: 10.1593/neo.06274.


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 kappaB (NFkappaB), 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 NFkappaB site. Furthermore, NFkappaB inhibition downregulated IL-6 gene and protein expression, and decreased the release of multiple cytokines. Interestingly, interfering with NFkappaB function also prevented the autocrine/paracrine activation of STAT3 in HNSCC cells. These findings demonstrate a cross-talk between the NFkappaB and the STAT3 signaling systems, and support the emerging notion that HNSCC results from the aberrant activity of a signaling network.

MeSH terms

  • Carcinoma, Squamous Cell / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic*
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • I-kappa B Kinase / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Models, Biological
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Transcription Factors / metabolism


  • Interleukin-6
  • NF-kappa B
  • STAT3 Transcription Factor
  • Transcription Factors
  • I-kappa B Kinase