title: Molecular cross-talk between the NFkappaB and STAT3 signaling pathways in head and neck squamous cell carcinoma.
abstract: 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.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
authors.forename: Cristiane H
authors.initials: CH
authors.lastname: Squarize
authors.forename: Rogerio M
authors.initials: RM
authors.lastname: Castilho
authors.forename: Virote
authors.initials: V
authors.lastname: Sriuranpong
authors.forename: Decio S
authors.initials: DS
authors.lastname: Pinto
authors.forename: Jorge Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D051550:I-kappa B Kinase