Long non-coding RNA FOXP4-AS1 is a prognostic biomarker and associated with immune infiltrates in ovarian serous cystadenocarcinoma

Abstract

Background: FOXP4-AS1 expression participates in multiple signal pathways and has been previously reported in colorectal cancer, cervical cancer, and other cancer cells. However, its role on prognosis and immune infiltrates in ovarian serous cystadenocarcinoma (OVs) remains unclear. The purpose of our study was to investigate the expression of FOXP4-AS1 in OVs and its association with immune infiltrates, and determined its prognostic roles in OVs.

Methods: Using The Cancer Genome Atlas (TCGA) database, we retrieved FOXP4-AS1 expression and clinical information for 376 patients with OVs. Wilcoxon rank sum test was used to compare the expression of FOXP4-AS1 in OVs and normal ovarian tissue. Logistic regression was used to analyze the relationship between clinicopathologic features and FOXP4-AS1. Gene Set Enrichment Analysis (GSEA), and single sample Gene Set Enrichment Analysis (ssGSEA) was conducted to investigate the enrich pathways and functions and quantify the extent of immune cells infiltration for FOXP4-AS1. Kaplan-Meier method was used to generate survival curves, and Cox regression was used to analyze the relationship between FOXP4-AS1 and survival rate.

Results: High FOXP4-AS1 expression was significantly correlated with tumor FIGO stage (P = .026). Multivariate survival analysis showed that FOXP4-AS1was an independent prognostic marker for overall survival (OS; hazard ratio [HR]: 0.638; 95% confidence interval [CI]:0.467-0.871; P = .001) and disease-specific survival (DSS; HR: 0.649; CI: 0.476-0.885; P = .006). GSEA showed that High FOXP4-AS1 expression may active programmed cell death 1 (PD-1) signaling, the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) pathway, the B cell receptor signaling pathway, apoptosis, fibroblast growth factor receptor (FGFR) signaling, and the Janus-activated kinase signal transducers and activators of transcription (JAK-STAT) signaling pathway. FOXP4-AS1 expression was negatively correlated with markers of immune cells, including aDC, cytotoxic cells and neutrophils.

Conclusion: High FOXP4-AS1 expression has the potential to be a prognostic molecular marker of favorable survival in OVs.

Figure 1

Clinical correlation and prognosis analysis of FOXP4-AS1 in ovarian serous cystadenocarcinoma patients in the TCGA cohort. Association of FOXP4-AS1 expression with FIGO stage (A), statistical analysis method: Kruskal–Wallis rank sum test. Relationship between FOXP4-AS1 expression and overall survival (B). Relationship between FOXP4-AS1 expression and disease-specific survival (C). TCGA = The Cancer Genome Atlas.

Figure 2

Relationship between FOXP4-AS1 expression and clinical characteristics of ovarian serous cystadenocarcinoma patients. Association of FOXP4-AS1 expression with clinicopathologic characteristics including histologic grade (A), tumor status (B), primary therapy outcome (C), residual tumor (D), lymphatic invasion (E), and venous invasion (F) in patients with ovarian serous cystadenocarcinoma in The Cancer Genome Atlas cohort. CR = complete remission, NRD = no residual disease, PD = progressive disease, PR = partial remission, RD = residual disease, SD = stable disease. Analysis between the two groups: Wilcoxon rank sum test.

Figure 3

Enrichment plots from gene set enrichment analysis (GSEA). GSEA results showing differential enrichment of PD-1 signaling (A), CTLA4 pathway (B), B cell receptor signaling pathway (C), apoptosis (D), signaling by FGFR (E), JAK-STAT signaling pathway (F) in FOXP4-AS1-related ovarian cancer. ES = enrichment score, FDR = false discovery rate, NES = normalized ES, p-adjust = adjusted P-value.

Figure 4

Correlation analysis between FOXP4-AS1 and related immune cell markers in ovarian serous cystadenocarcinoma. Correlation analysis between FOXP4-AS1 expression and immune cells (A); Correlation analysis between FOXP4-AS1 expression and levels of DC cell infiltration markers (B) and those of cytotoxic cells (C) and neutrophils (D).