title: Significance of interleukin-6 signaling in the resistance of pharyngeal cancer to irradiation and the epidermal growth factor receptor inhibitor.
abstract: OBJECTIVE
  Tumor eradication by chemoradiotherapy for pharyngeal cancer has not been particularly successful. Targeting epithelial growth factor receptor (EGFR) could be a potential treatment strategy providing additional benefits, but only a subset of these tumors gives a clinically significant response to EGFR inhibitors. The aim has been to identify the role of interleukin-6 (IL-6) signaling and its predictive power in the treatment response of pharyngeal cancer.
  
  
  METHODS
  Human pharyngeal cancer cell lines, including the hypopharyngeal cancer cell line FaDu and its derived cell line FaDu-C225-R, were selected. Changes in tumor growth, response to treatment, and responsible signaling pathway were investigated in vitro. Furthermore, 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining, and correlations were made between levels of IL-6, IL-6 receptor (IL-6R), p-AKT, and p-STAT3 expression and the clinical outcome of patients.
  
  
  RESULTS
  In vitro, either extrinsic IL-6 stimulation of cancer cells or intrinsically activated IL-6 signaling detected in FADu-C225-R cells results in resistance to irradiation and EGFR inhibitor. Blocking IL-6 signaling attenuated aggressive tumor behavior and sensitized the cells to treatments. The responsible mechanisms included decreased p-STAT3, less nuclear translocation of EGFR, and subsequently attenuated epithelial-mesenchymal transition. Regarding clinical data, staining of p-STAT3 and IL-6 was significantly linked with lower response rates to treatments and shorter survival in pharyngeal cancer patients.
  
  
  CONCLUSIONS
  IL-6 and p-STAT3 may be significant predictors of pharyngeal carcinoma, and regulating IL-6 signaling can be considered a promising therapeutic approach.
authors.affiliation: Department of Hematology and Oncology, Chang Gung Memorial Hospital at Chiayi, Taiwan.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chen
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chen
authors.forename: Chang-Hsien
authors.initials: CH
authors.lastname: Lu
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Wang
authors.forename: Paul-Yang
authors.initials: PY
authors.lastname: Lin
authors.forename: Kuan-Der
authors.initials: KD
authors.lastname: Lee
authors.forename: Miao-Fen
authors.initials: MF
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000378:metabolism*; D010610:Pharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011836:Radiation Tolerance / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D015850:Interleukin-6; D009363:Neoplasm Proteins; D051057:Proto-Oncogene Proteins c-akt; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors