Clinicopathological significance of cathepsin D expression in non-small cell lung cancer is conditional on apoptosis-associated protein phenotype: an immunohistochemistry study.

Cathepsin D is a well-known peptidase which belongs to the family of aspartic peptidases. It has been found to be overexpressed in many malignant tumors and associated with cancer metastasis and clinical outcome. However, its function in cancers remains controversial. Recently, increasing evidence shows that cathepsin D may play important roles in cell apoptosis. In the current study, we examined the expression of cathepsin D and a group of apoptosis-associated proteins including bcl-2, caspase 3, fas, fasL, p53, and survivin in nonsmall cell lung cancer (NSCLC) tissues to investigate the possible association between cathepsin D and these apoptosis-associated proteins and the clinicopathological features using immunohistochemistry. Cathepsin D expression was detected in cancer tissues including cancer cells (positive rate 64.5%(49/76)) and stromal parts including leukocytes, fibroblasts, capillary endothelial cells, and the matrix. No significant difference was found between the expression of cathepsin D in cancer cells and the corresponding non-tumor portions including bronchial epithelia and submucosal glands (positive rate 53.3% (8/15)) (p>0.05). Immunofluorescence study on formalin-fixed, paraffin-embedded specimens confirmed the cytoplasmic expression of cathepsin D in cancer cells and non-tumor portions. Western blot study detected both mature and immature forms of cathepsin D in lung and NSCLC tissues, while the expression level of neither form showed a significant difference between these tissues (p>0.05). Positive association was found between cathepsin D expression and fas status (p<0.01) but not with the other apoptosis-associated proteins (p>0.05) in cancer cells. Cathepsin D expression alone was not associated with any of the clinicopathological features (p>0.05), while multiplemarker analysis revealed that two immunostaining phenotypes based on the expression of cathepsin D and one of the apoptosis-associated proteins, namely, cathepsin D+/caspase 3- and cathepsin D+/p53+ showed clinicopathological significance. The cathepsin D+/caspase 3- group was associated with advanced tumor node metastasis stages (III and IV) (p<0.05), while the cathepsin D+/p53+ group was associated with lymph node metastasis (p<0.05). The present findings indicate that the expression of cathepsin D in non-small cell lung cancer may have possible contributions to cancer development which is conditional on apoptosis-associated protein phenotype.