TY - JOUR
T1 - Inverse expression of survivin and reprimo correlates with poor patient prognosis in gastric cancer
AU - Cerda-Opazo, Paulina
AU - Valenzuela-Valderrama, Manuel
AU - Wichmann, Ignacio
AU - Rodríguez, Andrés
AU - Contreras-Reyes, Daniel
AU - Fernández, Elmer A.
AU - Carrasco-Aviño, Gonzalo
AU - Corvalán, Alejandro H.
AU - Quest, Andrew F.G.
N1 - Publisher Copyright:
© Cerda-Opazo et al.
PY - 2018
Y1 - 2018
N2 - BACKGROUND: The objective of the study was to determine the relationship between Survivin and Reprimo transcript/protein expression levels, and gastric cancer outcome. METHODS: In 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 paraffinembedded 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. RESULTS: cBioPortal 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). CONCLUSIONS: TCGA 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.
AB - BACKGROUND: The objective of the study was to determine the relationship between Survivin and Reprimo transcript/protein expression levels, and gastric cancer outcome. METHODS: In 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 paraffinembedded 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. RESULTS: cBioPortal 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). CONCLUSIONS: TCGA 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.
KW - Gastric cancer
KW - Reprimo
KW - Survivin
KW - TCGA
UR - https://www.scopus.com/pages/publications/85042563038
U2 - 10.18632/oncotarget.24402
DO - 10.18632/oncotarget.24402
M3 - Article
C2 - 29560115
AN - SCOPUS:85042563038
SN - 1949-2553
VL - 9
SP - 12853
EP - 12867
JO - Oncotarget
JF - Oncotarget
IS - 16
ER -
