title: Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps.
abstract: BACKGROUND
  A number of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) are resistant to oral corticosteroids. Mucin 1 (MUC1) shows anti-inflammatory properties, and its cytoplasmic tail (CT) interacts with transcription factors, facilitating their nuclear translocation. Because glucocorticoid receptor (GR) nuclear translocation is key to the anti-inflammatory effect of corticosteroids, we hypothesized that MUC1 is involved in the effectiveness of corticosteroids.
  
  
  OBJECTIVE
  To analyze the role of MUC1 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved.
  
  
  METHODS
  Seventy-three patients with CRSwNP took oral corticosteroids for 15 days. Corticosteroid resistance was evaluated by nasal endoscopy. The expression of MUC1 and MUC1 CT was evaluated by real-time PCR, Western blotting, and immunohistochemistry. Beas-2B knockdown with RNA interference for MUC1 (siRNA-MUC1) was used to analyze the role of MUC1 in the anti-inflammatory effects of dexamethasone.
  
  
  RESULTS
  Nineteen patients had nasal polyps that were resistant to oral corticosteroids (NP-CR). MUC1 expression was downregulated in these patients. Primary epithelial cells from patients with NP-CR were insensitive to the anti-inflammatory effects of dexamethasone. In siRNA-MUC1 Beas-2B, dexamethasone showed weaker anti-inflammatory effects, a reduced inhibition of phospho-extracellular-signal-regulated kinases 1/2, a less severe mitogen-activated protein kinase phosphatase 1 increase, and a reduced GR nuclear translocation. Immunoprecipitation experiments revealed that MUC1-CT and GRα form protein complexes and translocate to the nucleus in response to dexamethasone. MUC1-CT-GRα complex was downregulated in NP-CR tissue.
  
  
  CONCLUSIONS
  MUC1-CT participates in the corticosteroid response that mediates GRα nuclear translocation. The low expression of MUC1 in patients with CRSwNP may participate in corticosteroid resistance.
authors.affiliation: Clinical Research Unit, University General Hospital Consortium, Valencia, Spain; Department of Biotechnology, Universidad Politécnica de Valencia, Valencia, Spain; Research Foundation of General Hospital of Valencia, Valencia, Spain. Electronic address: xmilara@hotmail.com.
authors.forename: Javier
authors.initials: J
authors.lastname: Milara
authors.affiliation: Research Foundation of General Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Peiró
authors.affiliation: Rhinology Unit, University General Hospital Consortium, Valencia, Spain; Department of Medicine, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Armengot
authors.affiliation: Rhinology Unit, University General Hospital Consortium, Valencia, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Frias
authors.affiliation: Research Foundation of General Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Anselm
authors.initials: A
authors.lastname: Morell
authors.affiliation: Research Foundation of General Hospital of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Serrano
authors.affiliation: Clinical Research Unit, University General Hospital Consortium, Valencia, Spain; Research Foundation of General Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002908:Chronic Disease; D015536:Down-Regulation; D004351:Drug Resistance / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D018396:Mucin-1 / Q000235:genetics*; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D009298:Nasal Polyps / Q000150:complications; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D012220:Rhinitis / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012852:Sinusitis / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D018396:Mucin-1; D011965:Receptors, Glucocorticoid; D051193:Toll-Like Receptors; C411470:glucocorticoid receptor alpha
keywords: MUC1; chronic rhinosinusitis; corticosteroid resistance; glucocorticoid receptor; nasal polyp