Abstract
BACKGROUNDThe objective of the study was to determine the relationship between Survivin and Reprimo transcript/protein expression levels, and gastric cancer outcome.METHODSIn silico correlations between an agnostic set of twelve p53-dependent apoptosis and cell-cycle genes were explored in the gastric adenocarcinoma TCGA database, using cBioPortal. Findings were validated by regression analysis of RNAseq data. Separate regression analyses were performed to assess the impact of p53 status on Survivin and Reprimo. Quantitative reverse-transcription PCR (RT-qPCR) and immunohistochemistry confirmed in silico findings on fresh-frozen and paraffin-embedded gastric cancer tissues, respectively. Wild-type (AGS, SNU-1) and mutated p53 (NCI-N87) cell lines transfected with pEGFP-Survivin or pCMV6-Reprimo were evaluated by RT-qPCR and Western blotting. Kaplan-Meier method and Long-Rank test were used to assess differences in patient outcome.RESULTScBioPortal analysis revealed an inverse correlation between Survivin and Reprimo expression (Pearson’s r= −0.3, Spearman’s ρ= −0.55). RNAseq analyses confirmed these findings (Spearman’s ρ= −0.37, p<4.2e-09) and revealed p53 dependence in linear regression models (p<0.05). mRNA and protein levels validated these observations in clinical samples (p<0.001). In vitro analysis in cell lines demonstrated that increasing Survivin reduced Reprimo, while increasing Reprimo reduced Survivin expression, but only did so in p53 wild-type gastric cells (p<0.05). Survivin-positive but Reprimo-negative patients displayed shorter overall survival rates (p=0.047, Long Rank Test) (HR=0.32; 95%IC: 0.11-0.97; p=0.044).CONCLUSIONSTCGA RNAseq data analysis, evaluation of clinical samples and studies in cell lines identified an inverse relationship between Survivin and Reprimo. Elevated Survivin and reduced Reprimo protein expression correlated with poor patient prognosis in gastric cancer.
Highlights
Gastric cancer is the third leading cause of cancerrelated deaths worldwide, with 951,000 new cases and 723,000 deaths in 2012 [1]
In vitro analysis in cell lines demonstrated that increasing Survivin reduced RPRM Inhibitor-of-apoptosis protein (Reprimo), while increasing Reprimo reduced Survivin expression, but only did so in p53 wild-type gastric cells (p
Elevated Survivin and reduced Reprimo protein expression correlated with poor patient prognosis in gastric cancer
Summary
Gastric cancer is the third leading cause of cancerrelated deaths worldwide, with 951,000 new cases and 723,000 deaths in 2012 [1]. Genomically stable tumors are enriched for Lauren’s class diffuse-type gastric cancer and recurrent CDH1, as well as RHOA mutations. Tumors with chromosomal instability are enriched for Lauren’s class intestinal-type gastric cancer, with frequent mutations in the tumor protein p53 (TP53), and located at the gastroesophageal junction [2]. As in many cancers, deregulation in the expression of cell cycle and apoptosis-related genes, as well as loss of functional p53 play an important role in disease development and progression. We focused our analysis on two cell cycle/apoptosis proteins Survivin (BIRC5) and Reprimo (RPRM). The objective of the study was to determine the relationship between Survivin and Reprimo transcript/protein expression levels, and gastric cancer outcome
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