title: Tristetraprolin regulates interleukin-6, which is correlated with tumor progression in patients with head and neck squamous cell carcinoma.
abstract: BACKGROUND
  Tumor-derived cytokines play a significant role in the progression of head and neck squamous cell carcinoma (HNSCC). Targeting proteins, such as tristetraprolin (TTP), that regulate multiple inflammatory cytokines may inhibit the progression of HNSCC. However, TTP's role in cancer is poorly understood. The goal of the current study was to determine whether TTP regulates inflammatory cytokines in patients with HNSCC.
  
  
  METHODS
  TTP messenger RNA (mRNA) and protein expression were determined by quantitative real-time-polymerase chain reaction (Q-RT-PCR) and Western blot analysis, respectively. mRNA stability and cytokine secretion were evaluated by quantitative RT-PCR and enzyme-linked immunoadsorbent assay, respectively, after overexpression or knockdown of TTP in HNSCC. HNSCC tissue microarrays were immunostained for interleukin-6 (IL-6) and TTP.
  
  
  RESULTS
  TTP expression in HNSCC cell lines was found to be inversely correlated with the secretion of IL-6, vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE(2) )(.) Knockdown of TTP increased mRNA stability and the secretion of cytokines. Conversely, overexpression of TTP in HNSCC cells led to decreased secretion of IL-6, VEGF, and PGE(2) . Immunohistochemical staining of tissue microarrays for IL-6 demonstrated that staining intensity is prognostic for poor disease-specific survival (P = .023), tumor recurrence and development of second primary tumors (P = .014), and poor overall survival (P = .019).
  
  
  CONCLUSIONS
  The results of the current study demonstrated that down-regulation of TTP in HNSCC enhances mRNA stability and promotes secretion of IL-6, VEGF, and PGE(2) . Furthermore, high IL-6 secretion in HNSCC tissue is a biomarker for poor prognosis. In as much as enhanced cytokine secretion is associated with poor prognosis, TTP may be a therapeutic target to reduce multiple cytokines concurrently in patients with HNSCC.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Van Tubergen
authors.forename: Robert
authors.initials: R
authors.lastname: Vander Broek
authors.forename: Julia
authors.initials: J
authors.lastname: Lee
authors.forename: Gregory
authors.initials: G
authors.lastname: Wolf
authors.forename: Thomas
authors.initials: T
authors.lastname: Carey
authors.forename: Carol
authors.initials: C
authors.lastname: Bradford
authors.forename: Mark
authors.initials: M
authors.lastname: Prince
authors.forename: Keith L
authors.initials: KL
authors.lastname: Kirkwood
authors.forename: Nisha J
authors.initials: NJ
authors.lastname: D'Silva
mesh_terms: D002277:Carcinoma / Q000276:immunology / Q000473:pathology; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness; D018307:Neoplasms, Squamous Cell / Q000276:immunology / Q000473:pathology; D020871:RNA Stability; D000077195:Squamous Cell Carcinoma of Head and Neck; D051816:Tristetraprolin / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D015850:Interleukin-6; D051816:Tristetraprolin; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases