The Prognostic Significance of NEDD9 Expression in Human Cancers: A Systematic Review, Meta-Analysis, and Omics Exploration

Abstract

Background: Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is considered an important factor in the progression of cancer, acting as a modulator of cellular migration, adhesion, and metastatic potential. Its significance as a prognostic factor, however, remains unclear, which necessitated a comprehensive review and meta-analysis.

Methods: Our study followed the PRISMA guidelines, analyzing studies from major databases including PubMed, Embase, and Cochrane. Our eligibility criteria included studies evaluating NEDD9 expression in relation to cancer prognosis and outcomes such as overall survival (OS), progression-free survival (PFS), disease-free Survival (DFS), recurrence-free survival (RFS), and cancer-specific survival (CSS). We used random-effects and fixed-effect models for meta-analysis, and we validated our findings by comparative analysis using data from external cohorts like The Cancer Genome Atlas (TCGA).

Results: The analysis of 27 studies with 3915 patients demonstrated a significant relationship between NEDD9 expression and poor OS as indicated by the pooled meta-analysis outcome across all included cancers (HR: 1.81, 95% CI: 1.38-2.37). A significant effect on PFS/DFS/RFS/CSS was also found (HR: 2.14, 95% CI: 1.42-3.23). Variations in survival across different types of cancer were indicated by subgroup analysis. NEDD9 expression was correlated with various immune cells across cancer types according to immune infiltration analysis. Protein-protein interaction (PPI) analysis indicated significant interactions involving NEDD9, suggesting mechanisms which influence tumor behavior and response to treatment.

Conclusion: Our results suggest that NEDD9 is a significant prognostic marker in several human cancers. As a result of its central role in cancer progression and prognosis, it presents a promising target for therapeutic interventions. Our study highlights the importance of further research into the biology of NEDD9 and its therapeutic potential.

Keywords: NEDD9 protein; cancer metastasis; gene expression profiling; human; meta-Analysis; oncology; prognostic biomarkers; signal transduction; survival analysis; systematic review; the cancer genome atlas.

Figure 1.

(a) PRISMA flowchart; (b) QUIPS quality assessment.

Figure 2.

Meta-analysis of hazard ratios for overall survival.

Figure 3.

Forest plots for meta-analysis on (a) PFS/RFS/CSS, (b) OS for lung cancers, and (c) OS for gastrointestinal cancers.

Figure 4.

Funnel plots for (a) OS, and (b) PFS/RFS/CSS.

Figure 5.

TCGA analysis and validation across different human cancers. (a) Proportions of somatic copy number alterations (sCNAs) for NEDD9, (b) NEDD9 expression profiles in tumor/normal samples, (c) Kaplan meier (KM) curve for selected gastrointestinal (GI) cancers (Outcome: OS), (d) KM curve for selected GI cancers (Outcome: DFS), (e) KM curve for STAD (Outcome: OS), (f) KM curve for LUAD (Outcome: OS), (g) KM curve for UVM (OS), and (h) heatmap for NEDD9 expression and death risk-related scores adjusted to cancer stage.

Figure 6.

(a) Protein-protein interaction (PPI) network for NEDD9 using STRING, (b) general functional enrichment analysis, (c) tissue-related enrichment, (d) cancer-related enrichment, (e) immune-related enrichment, and (f) heatmap for cancer-related pathway activation/inhibition and NEDD9 expression.

Figure 7.

(a) ImmuCellAI immune-infiltration heatmap (* indicates P < 0.05, # indicates FDR < 0.05), (b) TIMER cancer-associated fibroblasts (CAFs), and (c) MDSC infiltration heatmap. Abbreviations: DC, dendritic cells; MAIT, mucosal-associated invariant T cells; NK, natural killer cells; NKT, natural killer T cells; Th, T helper cells; MDSC, myeloid derived suppressor cells.

Figure 8.

(a) Human Protein Atlas (HPA) analysis of the percentages of patients with medium/high NEDD9 protein expression in different human cancers and with different antibodies. (b) Differential protein expression analysis of NEDD9 in selected human cancers from CPTAC database. Abbreviations: NS, non-significant; * P < 0.05.