Secretory leukocyte protease inhibitor promotes the tumorigenic and metastatic potential of cancer cells

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Abstract
Because of their ability to inhibit proteases, protease inhibitors have generally been considered to counteract tumor progression and metastasis. However, expression of serine protease inhibitors (SPIs) in tumors is often associated with poor prognosis of cancer patients. Moreover, there is growing evidence that SPIs may even promote malignancy of cancer cells, opening new avenues for their use as biomarkers in malignancy. To isolate cancer promoting genes, we applied the suppression subtractive hybridization method to low-malignant Lewis Lung Carcinoma 3LL-S versus high-malignant 3LL-S-sc cells. This resulted in the identification of the SPIsecretory leukocyte protease inhibitor(SLPI), as one of the genes whose expression was higher in 3LL-S-sc than in 3LL-S cells. By stable transfection of 3LL-S cells with mouse or humanSLPI, we demonstrated that elevated levels ofSLPIexpression increased both the tumorigenicity and lung-colonizing potential of 3LL-S cells. Moreover, we showed that this function ofSLPIdepended on its protease inhibitory capacity. Our results also reveal that althoughSLPIenhanced the proliferation of 3LL-S cellsin vitro, its promalignant activityin vivowas not solely due to its effect on cell proliferation. In this study, we report a causal role forSLPIin the malignant behavior of cancer cells, underscoring the potential malignancy-promoting activities of SPIs.

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