Abstract
ObjectivesCathepsin K, a lysosomal cysteine protease, is expressed in the tumor microenvironment (TME) of skin carcinoma, but nothing is known about cathepsin K in oral tongue squamous cell carcinoma (OTSCC). Our aim was to describe the expression of cathepsin K in invasive OTSCC in vitro and in a series of clinical cancer specimens.Materials and MethodsOTSCC invasion in vitro was studied using invasive HSC-3 tongue carcinoma cells in 3D organotypic models. In total, 121 mobile tongue OTSCCs and 10 lymph node metastases were analyzed for cathepsin K expression. The association between cathepsin K expression and clinicopathological factors was evaluated.ResultsCysteine protease inhibitor E64 and cathepsin K silencing significantly (p<0.0001) reduced HSC-3 cell invasion in the 3D models. Cathepsin K was expressed in a majority of carcinoma and metastatic cells, but the expression pattern in carcinoma cells did not correlate with clinical parameters. Instead, the weak expression of cathepsin K in the invasive TME front correlated with increased overall recurrence (p<0.05), and in early-stage tumors this pattern predicted both cancer recurrence and cancer-specific mortality (p<0.05 and p<0.005, respectively).ConclusionsCathepsin K is expressed in OTSCC tissue in both carcinoma and TME cells. Although the diminished activity and expression in aggressive tongue HSC-3 cells reduced 3D invasion in vitro, the amount of cathepsin K in carcinoma cells was not associated with the outcome of cancer patients. Instead, cathepsin K in the invasive TME front seems to have a protective role in the complex progression of tongue cancer.
Highlights
Proteases are an integral part of the maintenance of the mesodermal connective tissue system, playing a fundamental role in processes from early development to growth and homeostasis [1,2,3,4,5,6,7,8,9,10]
Cathepsin K was expressed in a majority of carcinoma and metastatic cells, but the expression pattern in carcinoma cells did not correlate with clinical parameters
Cathepsin K is expressed in oral tongue squamous cell carcinoma (OTSCC) tissue in both carcinoma and tumor microenvironment (TME) cells
Summary
Proteases are an integral part of the maintenance of the mesodermal connective tissue system, playing a fundamental role in processes from early development to growth and homeostasis [1,2,3,4,5,6,7,8,9,10]. Cathepsin K is largely absent in skin, whereas dermal fibroblasts of surgical scars present strong cytoplasmic cathepsin K expression [11] This suggests that cathepsin K is important for modeling of the dermal extracellular matrix. Codriansky et al [20] have shown that cathepsin K is a key factor in skin homeostasis, in which a decline in cathepsin K response in UVA-damaged fibroblasts results in an accumulation of abnormal elastin in the extracellular space. This confirms that cathepsin K is essential to the dynamic equilibrium between live mesenchymal cells and matrix synthesis and degradation
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