Impact of KSRP on Post-transcriptional Deregulation of IL-8, IL-1b, TNF-α, CXCR2 and IL-1R Expression and Consequently on Cell Motility and Invasiveness in Melanoma Cells

Background. The pleiotropic KH Splicing Regulatory Protein (KSRP) is considered a checkpoint in inflammation since it regulates the expression of several inflammatory cytokines, binding to their mRNAs and committing them to exosome-mediated degradation. Deregulation of this post-transcriptional control of gene expression is at the basis of a variety of pathological processes. Genes coding cytokines and cytokines receptors frequently undergoes post-transcriptional regulation: their altered expression generates a crosstalk between cancer cells and microenvironment that promotes cancer onset and progression. Having observed that KSRP RNA targets identified so far - IL-1b, IL-6, IL-8, iNOS, TNF-a, beta catenin and let7 family - are deregulated in invasive melanoma, we have hypothesized that KSRP could play a key role in melanoma progression. Methods. Biomolecular effects of positive or negative exogenous modulation of KSRP expression on human melanoma cell lines (A375, A375-M6, MeWo and M21) have been analyzed. Results. Here, we report the following evidences: 1) KSRP lowers expression of IL-8, IL-1b and TNF-a, already known as KSRP targets, by destabilizing their mRNAs; 3) KSRP binds the mRNAs of CXCR2 and IL-1R, two KSRP targets unraveled so far, and reduces their expression by lowering their mRNA stability; 4) KSRP overexpression causes a marked decrease of cell motility and invasiveness, and lowers the apoptosis threshold in response to UV irradiation. Conclusions. Our results strongly suggest that KSRP could contribute to melanoma progression. The evidences reported here could be the basis for future studies aimed to modulate KSRP in melanoma by interfering with the multiple factors promoting onset and progression of this severe malignancy.