The role of the antileukoprotease SLPI in smoking‐induced human papillomavirus‐independent head and neck squamous cell carcinomas

• Published in: International journal of cancer Vol. 134; no. 6; pp. 1323 - 1334
• Main Authors: Quabius, Elgar Susanne, Möller, Paul, Haag, Jochen, Pfannenschmidt, Saskia, Hedderich, Jürgen, Görögh, Tibor, Röcken, Christoph, Hoffmann, Markus
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 15.03.2014; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Aged, 80 and over; AhR gene; Annexin A2 - genetics; Annexin A2 - metabolism; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer; Carcinoma, Squamous Cell - chemically induced; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - virology; Case-Control Studies; Cyclin-Dependent Kinase Inhibitor p16; DNA, Viral; Female; Follow-Up Studies; Head & neck cancer; Head and Neck Neoplasms - chemically induced; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - virology; HNSCC; HPV; Human papillomavirus; Humans; Immunoenzyme Techniques; Male; Medical research; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Papillomaviridae; Papillomavirus Infections - metabolism; Papillomavirus Infections - pathology; Papillomavirus Infections - virology; Proteases; Real-Time Polymerase Chain Reaction; Secretory Leukocyte Peptidase Inhibitor - genetics; Secretory Leukocyte Peptidase Inhibitor - metabolism; SLPI; Smoking; Smoking - adverse effects; Tobacco, tobacco smoking; Toxicology; Tumors; Young Adult; Tobacco smoking; Papovaviridae; Malignant tumor; HPV; Infection; Papillomavirus; Virus; Human papillomavirus; Secretory leukocyte protease inhibitor; Cancerology; SLPI; Viral disease; HNSCC; smoking; ENT disease; Head and neck cancer; Head and neck squamous cell carcinoma; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28462

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 (r2 = 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. What's new? With the incidence of human papillomavirus (HPV) head and neck squamous cell carcinoma (HNSCC) on the rise in non‐smokers, a better understanding of the relationship between HPV infection, smoking, and oncogenesis is needed. This study demonstrates that smoking (in HNSCC and non‐HNSCC patients) and nicotine incubation (ex vivo) increases expression of secretory leukocyte peptidase inhibitor (SLPI). Significant correlations between smoking and SLPI expression in tumors and mucosa of HNSCC and non‐HNSCC patients were established. In addition, all HPV‐positive patients showed no or low SLPI expression. The findings suggest that SLPI upregulation via smoking may protect against HPV infection.