The interaction of smoking habit, SLPI and AnxA2 in HPV associated head and neck and other cancers.

Six own studies confirm a correlation between smoking, expression of the secretory leukocyte protease inhibitor (SLPI, an antileukoproteinase) and expression of Annexin A2 (AnxA2), and their influence on human papilloma virus (HPV)-infections. SLPI and HPV are ligands of AnxA2. This correlation was tested on 928 tissue samples from 892 patients in six independent studies [squamous cell carcinoma of the head and neck (HNSCC), n = 522; non-neoplastic tonsils n = 214; clinically normal mucosa, n = 93 (of these n = 57 were obtained from patients treated for non-malignant diseases and n = 36 were obtained from HNSCC-patients) and vulvar squamous cell carcinoma (VSCC) n = 99]. HPV-DNA-status was determined by GP5+/GP6+-PCR, followed in case of HPV-positivity by Sanger sequencing and RT-PCR using HPV-type specific primers. SLPI- and AnxA2-gene-expression was determined by RT-q-PCR; SLPI-protein-expression was additionally determined by immunohistochemistry (IHC); the data were correlated with each other and with patient characteristics. Smoking results in increased SLPI-gene- and protein- and AnxA2-gene-expression with significantly higher SLPI- than AnxA2-gene-expression. SLPI is decreased in non-smokers with a continuous AnxA2-surplus. HPV-status correlates with smoking habit, with smokers being mostly HPV-negative and non-smokers HPV-positive. We hypothesize that smoking leads to SLPI-overexpression with SLPI-binding to AnxA2. Thus, HPV cannot bind to AnxA2 but this seems pivotal for HPV-cell-entry. Smoking favors SLPI-expression resulting in HPV-negative carcinomas, while HPV-positive carcinomas are more common in non-smokers possibly due to a surplus of unbound AnxA2. In addition, the hypothesis may contribute to understand why smokers show increased oral HPV-prevalence in natural history studies but do not necessarily develop HPV-associated lesions.