title: The role of the antileukoprotease SLPI in smoking-induced human papillomavirus-independent head and neck squamous cell carcinomas.
abstract: Recently, we showed that increased SLPI levels prevent human papillomavirus (HPV) infections and metastasis in smoking-induced, non-HPV-driven head and neck squamous cell carcinoma (HNSCC). Here, we focus on the role of SLPI in non-HPV-driven HNSCC, investigating tumor tissue and non-neoplastic mucosa from the same patients and from non-HNSCC patients. Gene and protein expression of SLPI and gene expression of annexin 2 (a SLPI receptor), nicotine receptor (α7AChR) and arylhydrocarbon receptor (AhR) were analyzed in HNSCC patients (20 smokers; 16 nonsmokers). SLPI-results were correlated with the patients' HPV status. Non-neoplastic mucosa of HNSCC patients and normal mucosa from non-HNSCC individuals (18 smokers; 20 nonsmokers) was analyzed for the same parameters. Tissue of the inferior turbinate (n = 10) was incubated with nicotine for analysis of the same genes. SLPI gene expression in tumor tissue was 109.26 ± 23.08 times higher in smokers versus nonsmokers. Non-neoplastic mucosa of smokers showed also higher SLPI gene expression (10.49 ± 1.89-fold non-HNSCC; 18.02 ± 3.93-fold HNSCC patients). Annexin 2 gene expression was also increased in smokers. SLPI data were corroborated by immunohistochemistry. A nicotine dependent correlation between SLPI and annexin 2 gene expression (r(2) = 0.15, p < 0.001) was shown ex vivo. Nicotine and smoking increased α7AChR and AhR gene expression. Five patients, showing no/low SLPI expression, were HPV16-positive. A significant correlation between smoking and SLPI expression in tumors and to our knowledge for the first time in mucosa of HNSCC and non-HNSCC patients was established. Together with the finding that all patients with HPV infection showed no/low SLPI expression, these data support our intriguing hypothesis that smoking induced upregulated SLPI prevents HPV infections.
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Christian-Albrechts-University Kiel, D-24105, Kiel, Germany; Institute of Immunology, Christian-Albrechts-University Kiel, D-24105, Kiel, Germany.
authors.forename: Elgar Susanne
authors.initials: ES
authors.lastname: Quabius
authors.forename: Paul
authors.initials: P
authors.lastname: Möller
authors.forename: Jochen
authors.initials: J
authors.lastname: Haag
authors.forename: Saskia
authors.initials: S
authors.lastname: Pfannenschmidt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hedderich
authors.forename: Tibor
authors.initials: T
authors.lastname: Görögh
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D016022:Case-Control Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D060888:Real-Time Polymerase Chain Reaction; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*; D055815:Young Adult
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor
keywords: HNSCC; HPV; SLPI; smoking