title: IL-6 controls resistance to radiation by suppressing oxidative stress via the Nrf2-antioxidant pathway in oral squamous cell carcinoma.
abstract: BACKGROUND
  In promoting tumour malignancy IL-6 signalling is considered to have an important role. However, the biological roles of IL-6 on radiosensitivity in oral squamous cell carcinoma (OSCC) remain largely unclear. The objective of this study is to determine the effects and molecular mechanisms of IL-6 on radiosensitivity in OSCC.
  
  
  METHODS
  Two OSCC cell lines, and OSCC tissue samples with radioresistant cells were used. We examined the effects of IL-6, or tocilizumab, a humanised anti-human IL-6 receptor antibody, or both on radiosensitivity and DNA damage after X-ray irradiation in vitro. In addition, we investigated the involvement of the Nrf2-antioxidant pathway in IL-6-mediated radioresistant mechanisms using OSCC cell lines and tissues.
  
  
  RESULTS
  Increased levels of IL-6 suppressed radiation-induced cell death, and the blockade of IL-6 signalling by tocilizumab sensitised tumour cells to radiation. The radioresistant effect of IL-6 was associated with decreased DNA damage after radiation. We also found that IL-6 promotes the activation of not only the downstream molecule STAT3 but also the Nrf2-antioxidant pathway, leading to a significant decrease in oxidative stress by upregulating Mn-SOD.
  
  
  CONCLUSIONS
  These results indicate that the blockade of IL-6 signalling combined with conventional radiotherapy could augment the treatment response and survival rate in patients with radioresistant OSCC.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Matsuoka
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yoshida
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Hirosue
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Nagata
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Junki
authors.initials: J
authors.lastname: Sakata
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Arita
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.|Central Clinical Laboratory, Kumamoto University Hospital, Kumamoto 860-8556, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Fukuma
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Hidenao
authors.initials: H
authors.lastname: Ogi
authors.affiliation: Section of Oral Oncology, Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka 814-0193, Japan.
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Hiraki
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Radiation Oncology, Kumamoto University Hospital, Kumamoto 860-8556, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Toya
authors.affiliation: Department of Medical Imaging, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0976, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Murakami
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D011836:Radiation Tolerance / Q000502:physiology*; D011878:Radiotherapy / Q000379:methods; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014965:X-Rays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000975:Antioxidants; C508600:IL6 protein, human; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C502936:tocilizumab