Integrated analysis of the prognostic value of TP53 dependent etoposide-induced gene 24 in non-small cell lung cancer

• Published in: Biomedicine & pharmacotherapy Vol. 112; p. 108590
• Main Authors: Wang, Maofeng, Li, Peipei, Wan, Rugen, Liu, Xiyong
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.04.2019; Elsevier
• Subjects: Bioinformatics analysis; Etoposide-induced gene 24; Non-small cell lung carcinoma; Prognostic biomarker; TP53; ALK; Bioinformatics analysis; AD; NSCLC; OS; TFBS; EI24; Non-small cell lung carcinoma; HR; EGFR; DFS; SCC; TF; TKI; LA; Etoposide-induced gene 24; TP53; SQ; Prognostic biomarker
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.01.051

[Display omitted] •Expression of EI24 was reduced as with increased TP53 levels in TP53 wild type NSCLC.•EI24 is overexpressed in cancer sections of NSCLC and related with molecular subtypes of ALK fusion+ and EGFR wild type.•Overexpression of EI24 was significantly associated with poor outcome in NSCLC patients.•EI24 impacts poor overall survival in NSCLC patients with the TP53 wild type, but not those with mutated TP53.•YY1 might be a transcriptional factor of EI24 and impact poor outcome of NSCLC. Etoposide-induced gene 24 (EI24) is an induction target of TP53-mediated apoptosis in human cancer cells. The hypothesis of this study is that EI24 might be a prognostic biomarker of non-small cell lung carcinoma (NSCLC). Fourteen gene expression NSCLC datasets with follow-up information (a total of 2582 accessible cases) were collected from Asia, Europe and North America. The Kaplan-Meier and Cox analyses were applied to evaluate the relation between EI24 and the outcomes of NSCLC. A gene set enrichment analysis (GSEA) was used to explore EI24 and cancer-related gene signatures. EI24 was significantly upregulated in mutated TP53 NSCLC samples and significantly downregulated with the increase in the TP53 expression level in NSCLC. GSEA results suggested that EI24 significantly enriched metastasis and poor prognosis gene signatures. Meanwhile, EI24 was significantly upregulated in lung adenocarcinoma compared with normal lungs (p < 0.01). It was also highly expressed in the later TNM stages and the ALK fusion+, higher MYC gene copy and EGFR wild type subgroups (p < 0.05). The Kaplan-Meier analysis demonstrated that the expression of EI24 was significantly associated with poor overall survival and disease-free survival in a dose-dependent manner in GSE31210 dataset. The C-index of Cox model with EI24 is 0.70, that is better than that with MYC (0.51), KRAS (0.51) and EGFR (0.59), which indicates better prognostic performance of EI24. The prognostic significance of EI24 for overall survival of NSCLC was validated by pooled and meta-analysis on 14 datasets. The stratification analysis revealed that EI24 prognosticated poor overall survival (HR = 3.37, 95% CI = 1.39–9.62, p < 0.05) in the TP53 wild type subgroup, but not in the mutated TP53 NSCLC subgroup. Moreover, YY1 might transcriptionally regulate EI24 in a positive manner. EI24 is a potential prognostic biomarker and impacts poor outcome in NSCLC. The prognostic significance of EI24 might rely on TP53 status.