Human papillomavirus infection in head and neck cancer: The role of the secretory leukocyte protease inhibitor

Abstract

Abstract. We previously showed that secretory leukocyte protease inhibitor (SLPI) gene and protein expression is significantly lower in metastatic versus non-metastatic head and neck squamous cell carcinoma (HNSCC). However, we did not assess the human papillomavirus (HPV) status of these cases. Since SLPI plays a role in HIV and herpes simplex virus (HSV) infections, we hypothesized that SLPI may be involved in HPV-infected HNSCC. In HNSCC tissue (n=54), HPV DNA was determined and correlated with SLPI expression. Additionally, to investigate a possible role of smoking on SLPI expression in clinically normal mucosa, 19 patients treated for non-malignant diseases (non-HNSCC) were analyzed for SLPI expression and correlated with smoking habits. In HNSCC patients, SLPI expression showed a significant inverse correlation with HPV status. In patients with moderate/strong SLPI expression (n=19), 10.5% were HPV-positive. By contrast, patients with absent/weak SLPI expression (n=35), 45.7% were HPV-positive. Low SLPI expression was correlated with metastasis (P= 0.003) independent of HPV status. HPV-positivity was clearly associated with lymph node status (81.3% N1-3 cases). In smoking non-HNSCC patients (n=7), 42.9% showed absent/weak and 57.1% moderate/strong SLPI staining. In nonsmoking non-HNSCC patients (n=10) 83.3% showed absent/ weak and 16.7% moderate/strong SLPI expression. For the first time, a correlation between SLPI downregulation and HPV infection was demonstrated, suggesting that high levels of SLPI, possibly induced by environmental factors such as tobacco smoking, correlate with protective effects against HPV infection. SLPI may be a potential biomarker identifying head and neck cancer patients not at risk of developing metastases (SLPI-positive), and those at risk to be infected by HPV (SLPI-negative) and likely to develop metastases.

SLPI and AnxA2 expression in neoplasm-free palatine tonsils is associated with smoking habit of individuals

“…As shown previously (1)(2)(3), both the secretory leucocyte protease inhibitor (SLPI; an antiproteinase) and the membrane bound receptor Annexin A2 (AnxA2) showed higher expression levels in smokers in comparison to non-smokers. However, SLPI showed a clear surplus compared to AnxA2 in smokers vs. non-smokers whereas AnxA2 vs. SLPI showed a significant surplus in cases tested HPV-positive when compared to HPV-negative cases (1)(2)(3). Previous ex vivo data showed that SLPI expression in clinically healthy mucosa of the lower turbinates can be increased by incubation with nicotine (2).…”

Herpes simplex virus downregulation of secretory leukocyte protease inhibitor enhances human papillomavirus type 16 infection

“…We have previously provided evidence that HNSCC patients with lower SLPI levels are more likely to have HPV-positive cancers, demonstrating a correlation between reduced SLPI and increased HPV infection in vivo (Cordes et al, 2011;Hoffmann et al, 2013). With this observation in mind, we utilized the HSV-mediated reduced SLPI environment to examine the effect of HPV16 uptake and infection in vitro.…”

“…In addition to the aforementioned in vitro data, a strong inverse correlation exists between the expression of the innate immune protein SLPI, and the HPV status and degree of metastasis of HNSCC in vivo (Cordes et al, 2011;Hoffmann et al, 2013). Specifically, it was found that higher SLPI levels were correlated with lower HPV expression in vivo.…”

Salivary secretory leukocyte protease inhibitor (SLPI) and head and neck cancer: The Cancer Prevention Study II Nutrition Cohort

“…It is found in various bodily secretions, but is present in particularly high concentrations in the saliva [8]. The role of salivary SLPI in reducing transmission of HIV in the oral cavity has been well studied [9, 10], and there is growing evidence that SLPI may protect against oral HPV infection [11, 12]. Results from tumor studies suggest that SLPI may be associated with HNC carcinogenesis [7], metastasis [11, 13], and prognosis [14], although the exact mechanisms by which SLPI protects against HNC development and progression remain unclear.…”

“…The role of salivary SLPI in reducing transmission of HIV in the oral cavity has been well studied [9, 10], and there is growing evidence that SLPI may protect against oral HPV infection [11, 12]. Results from tumor studies suggest that SLPI may be associated with HNC carcinogenesis [7], metastasis [11, 13], and prognosis [14], although the exact mechanisms by which SLPI protects against HNC development and progression remain unclear. SLPI is believed to protect mucosal surfaces against proteolysis and epithelial tissue damage [15] by inhibiting neutrophil elastase, a serine protease produced by tumor and inflammatory cells that is known to induce tumor cell proliferation [16].…”