title: S100A8 is a novel therapeutic target for anaplastic thyroid carcinoma.
abstract: BACKGROUND
  Anaplastic thyroid carcinoma (ATC) is one of the most deadly human malignancies. It is 99% lethal, and patients have a median survival of only 6 months after diagnosis. Despite these grim statistics, the mechanism underlying the tumorigenic capability of ATC cells is unclear.
  
  
  OBJECTIVE
  S100A8 and S100A9 proteins have emerged as critical mediators in cancer. The aim was to investigate the expression and function of S100A8 and S100A9 in ATC and the mechanisms involved.
  
  
  METHODS
  We determined the expression of S100A8 and S100A9 in human ATC by gene array analysis and immunohistochemistry. Using RNAi-mediated stable gene knockdown in human ATC cell lines and bioluminescent imaging of orthotopic and lung metastasis mouse models of human ATC, we investigated the effects of S100A8 and S100A9 on tumorigenesis and metastasis.
  
  
  RESULTS
  We demonstrated that S100A8 and S100A9 were overexpressed in ATC but not in other types of thyroid carcinomas. In vivo analysis in mice using ATC cells that had S100A8 knocked down revealed reduced tumor growth and lung metastasis, as well as significantly prolonged animal survival. Mechanistic investigations showed that S100A8 promotes ATC cell proliferation through an interaction with RAGE, which activates the p38, ERK1/2 and JNK signaling pathways in the tumor cells.
  
  
  CONCLUSIONS
  These findings establish a novel role for S100A8 in the promoting and enhancing of ATC progression. They further suggest that the inhibition of S100A8 could represent a relevant therapeutic target, with the potential of enabling a more effective treatment path for this deadly disease.
authors.affiliation: Department of Otolaryngology (A.N.R., W.L., W.S., K.S., R-Y.L.), Head and Neck Surgery, St. Louis University School of Medicine, St Louis, Missouri 63104; Department of Cancer Biology (L.A.M., J.A.C.), Division of Hematology/Oncology (H.W.T.), and Division of Endocrinology (R.C.S.), Mayo Clinic, Jacksonville, Florida 32224; Department of Pathology and Immunology (R.C.), Washington University School of Medicine, St Louis, Missouri 63110.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Reeb
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Will
authors.initials: W
authors.lastname: Sewell
authors.forename: Laura A
authors.initials: LA
authors.lastname: Marlow
authors.forename: Han W
authors.initials: HW
authors.lastname: Tun
authors.forename: Robert C
authors.initials: RC
authors.lastname: Smallridge
authors.forename: John A
authors.initials: JA
authors.lastname: Copland
authors.forename: Kyle
authors.initials: K
authors.lastname: Spradling
authors.forename: Rebecca
authors.initials: R
authors.lastname: Chernock
authors.forename: Reigh-Yi
authors.initials: RY
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C000593871:AGER protein, human; D040501:Calgranulin A; D040502:Calgranulin B; D000067759:Receptor for Advanced Glycation End Products