Secretory Leukocyte Protease Inhibitor (SLPI) Expression and Tumor Invasion in Oral Squamous Cell Carcinoma

Abstract

Differential expression of secretory leukocyte protease inhibitor (SLPI) impacts on tumor progression. SLPI directly inhibits elastase and other serine proteases, and regulates matrix metalloproteinases, plasminogen activation, and plasmin downstream targets to influence invasion. We examined tissues from human oral squamous cell carcinoma (OSCC) for SLPI expression in parallel with proteases associated with tumor progression and evaluated their relationships using tumor cell lines. Significantly decreased SLPI was detected in OSCC compared to normal oral epithelium. Furthermore, an inverse correlation between SLPI and histological parameters associated with tumor progression, including stage of invasion, pattern of invasion, invasive cell grade, and composite histological tumor score was evident. Conversely, elevated plasmin and elastase were positively correlated with histological parameters of tumor invasion. In addition to its known inhibition of elastase, we identify SLPI as a novel inhibitor of plasminogen activation through its interaction with annexin A2 with concomitant reduced plasmin generation by macrophages and OSCC cell lines. In an in vitro assay measuring invasive activity, SLPI blocked protease-dependent tumor cell migration. Our data suggest that SLPI may possess antitumorigenic activity by virtue of its ability to interfere with multiple requisite proteolytic steps underlying tumor cell invasion and may provide insight into potential stratification of oral cancer according to risk of occult metastasis, guiding treatment strategies.

Matrix metalloproteinases in head and neck cancer: current perspectives

“…144 Tranexamic acid and SLPI have been evaluated for their potential to downregulate MMP activity by inhibiting plasminogen activation. 145,146 Other design strategies targeting the MMP catalytic domain Following disappointments with treatment outcomes with earlier anti-MMP regimes, design strategies soon shifted to more sophisticated, selective inhibitors, with fewer side effects. One such strategy focused on designing smallmolecule inhibitors that fit in size and shape with the variable S1′ deep cavity of the catalytic domain as an alternative approach to disrupting the strong catalytic zinc-binding activity using MMP12-inhibition models.…”

SLPI (secretory leukocyte peptidase inhibitor)

“…Also, it was described that SLPI plasma levels were elevated in lung cancer patients (Zelvyte et al 2004). More recently, low level of SLPI was detected in oral squamous cell carcinoma compared with normal oral epithelium (Wen et al 2011). Moreover, an inverse correlation was also reported between SLPI and histological parameters associated with tumor progression (Wen et al 2011).…”

“…More recently, low level of SLPI was detected in oral squamous cell carcinoma compared with normal oral epithelium (Wen et al 2011). Moreover, an inverse correlation was also reported between SLPI and histological parameters associated with tumor progression (Wen et al 2011). Interestingly, SLPI reduced the hepatic lung carcinoma metastasis (Wang et al 2006).…”

A link between interferon and augmented plasmin generation in exocrine gland damage in Sjögren's syndrome

“…In our recent studies, we demonstrated that in oral squamous cell carcinoma, heightened levels of plasmin occur in an environment of reduced expression of secretory leukocyte protease inhibitor (SLPI), which blunts plasminogen activation at the cell surface[14]. Moreover, SLPI directly inhibits macrophage MMP, possibly through inhibition of NFκB[15, 16], and plasmin activation through its interaction with annexin A2[14, 17] and the absence of SLPI is associated with enhanced proteolytic activity, delayed matrix accumulation, aberrant tissue repair and tumor invasion[14, 18–20]. In transcriptome analyses of minor salivary gland tissues from patients with SS, SLPI expression was reduced[5], suggesting that such pathways may be operational in salivary gland pathology.…”