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

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 SPI secretory 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 human SLPI, we demonstrated that elevated levels of SLPI expression increased both the tumorigenicity and lung-colonizing potential of 3LL-S cells. Moreover, we showed that this function of SLPI depended on its protease inhibitory capacity. Our results also reveal that although SLPI enhanced the proliferation of 3LL-S cells in vitro, its promalignant activity in vivo was not solely due to its effect on cell proliferation. In this study, we report a causal role for SLPI in the malignant behavior of cancer cells, underscoring the potential malignancy-promoting activities of SPIs.