Livin, a regulator of apoptosis protein, is deregulated in melanoma and serves as an independent prognostic factor—a study of 114 melanoma patients

Abstract

21006 Background: Inhibitor of Apoptosis Proteins (IAP) family members inhibit apoptosis mainly by direct binding and inhibition of caspases. We previously identified the IAP Livin and demonstrated that following strong apoptotic stimuli the protein was cleaved by effector caspases to produce a truncated form with paradoxical pro-apoptotic activity. We also demonstrated that Livin is overexpressed in melanoma (M) and plays a role in chemoresistance and survival. More recently we identified synonymous single nucleotide polymorphism (SNP) in Livin at position 528(C/T) that determines expression levels of Livin protein. We found that Livin is expressed in a monoalleic manner. Normal heterozygous samples express the 528T mRNA allele and the Livin protein is not expressed. The monoallelic regulation is lost in metastatic M and the Livin protein is expressed. Methods: This study included 114 M patients that were grouped into clinical categories according to prognosis. Correlation between Livin expression and clinical parameters was examined using ANOVA, chi-square test and Kaplan-Mayer curves. Results: We found that in primary cultures from 114 M patients high, low and absence of Livin protein expression were associated with the T/C, CC and TT genotypes, respectively, at the 528(C/T) polymorphic site. Correlation of Livin expression with overall survival was significant: high expression of the Livin protein was associated with bad prognosis; survival in patients with medium expression of Livin was significantly longer compared with those without livin expression For 23 patients samples were obtained both at diagnosis and upon disease progression. All 23 first tumor sample did not express the Livin protein. Remarkably, Livin was expressed in second tumor samples from 9 of the 23 patients.and was associated with poor prognosis. Conclusions: We found that Livin expression is an independent prognosis factor in malignant M. furthermore, we describe a direct correlation between the level of Livin protein expression and survival of M patients. We also provide evidence for a novel mechanism associating synonymous SNP with control over protein expression and its deregulation during tumor progression. No significant financial relationships to disclose.