The Tumor-Promoting Effect of TNF-α Involves the Induction of Secretory Leukocyte Protease Inhibitor

Abstract

According to the cancer immunoediting concept, inflammatory mediators play not only a critical role in promoting host protection against cancer but also contribute to cancer cell growth and survival. TNF-α is a critical factor in this network. However, the mechanisms underlying the tumor-promoting effect of TNF-α have not been fully elucidated yet. We previously reported that in vitro culture of Lewis lung carcinoma 3LL cells with TNF-α-producing macrophages resulted in enhanced resistance toward TNF-α-mediated lysis and increased malignancy of the 3LL cells. In this study, we analyzed the effects of endogenous TNF-α on TNF-α resistance and malignant behavior in vivo of low-malignant/TNF-α-sensitive 3LL-S cells and cancer cells derived from 3LL-S tumors that developed in wild-type or TNF-α−/− mice. Interestingly, 3LL-S cells acquired a malignant phenotype in vivo depending on the presence of host TNF-α, whereas acquisition of TNF-α resistance was TNF-α-independent. This result suggested that malignancy-promoting characteristics of 3LL-S cells other than TNF-α resistance are influenced in vivo by TNF-α. We previously identified the malignancy-promoting genes, secretory leukocyte protease inhibitor (SLPI) and S100A4, as being up-regulated in 3LL-S cells upon their s.c. growth in wild-type mice. In this study, we show that SLPI, but not S100A4, was induced in 3LL-S cells both in vitro and in vivo by TNF-α, and that silencing of in vivo induced 3LL-S SLPI expression using RNA interference abrogated in vivo progression but did not influence TNF-α resistance. These data indicate that SLPI induction may be one mechanism whereby TNF-α acts as an endogenous tumor promoter.

Effect of secretory leukocyte protease inhibitor on migration and invasion of human KB oral carcinoma cells

“…In this study, the SLPI-treated KB cells showed a strong increase in migration and invasion but the migration and invasion of KB cells were reduced by SLPI-siRNA, supporting the results of the in vitro wound healing assay as well as the agonistic effect of SLPI on cancer development (Devoogdt et al 2003(Devoogdt et al , 2004. Another study reported similar findings in that the down-regulation of SLPI expression reduces the capacity to form tumors in 3LL-S cells (Devoogdt et al 2006). In summary, these results showed that SLPI increases the proliferation, migration and invasion of KB cells, which suggests that SLPI is involved in the metastasis of oral carcinoma cells.…”

WAP four-disulfide core domain protein 2 mediates the proliferation of human ovarian cancer cells through the regulation of growth- and apoptosis-associated genes

“…WFDC2 contains two WAP structural domains and belongs to the WAP protein family. Previous research indicates that proteins with a WFDC motif usually exhibit the following: A number of WAP proteins have been mapped to human chromosome 20q12-13.1, a region amplified in several types of cancers leading to the proposal that genes located on this region of chromosome 20 play a role in carcinogenesis and tumor progression (6,9); exhibit anti-inflammatory and antimicrobial activity against Gram-negative bacteria and viruses by regulating the NF-κB activity (17)(18)(19); regulate cell growth (13,14,20,21) and regulate angiogenesis and cell spread by the interference of the leucocyte cell-derived and tumor cell-derived proteinase and cytokines (8,12,22,23). Despite these findings the precise function of WFDC2 remains unknown.…”

“…The expression of SLPI was positively correlated with the increased expression of the cell cycle progression factor, cyclin D1, and its causal role in the promotion of malignant behavior was also demonstrated in lung carcinomous cells stably transfected with human SLPI-expression constructs (8,(12)(13)(14). Elafin was reported to be overexpressed in late-stage, high-grade serous ovarian carcinomas and to correlate with poor overall survival (15).…”

Tumor immunoediting and immunosculpting pathways to cancer progression

“…TNF-α is also known to augment its own activity by promoting the release of other soluble mediators. Devoogdt and colleagues recently showed, using gene silencing, that Secretory Leukocyte Protease Inhibitor (SLPI), induced by TNF-α in lung carcinoma cells, was involved in the tumor-promoting activity of TNF-α by an as of yet unknown mechanism [69][70][71].…”