GJA1 Expression and Its Prognostic Value in Cervical Cancer

Abstract

Gap Junction Protein Alpha 1 (GJA1) belongs to the gap junction family and has been widely studied in cancers. We evaluated the role of GJA1 in cervical cancer (CC) using public data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. The difference of GJA1 expression level between CC and normal tissues was analyzed by the Gene Expression Profiling Interactive Analysis (GEPIA), six GEO datasets, and the Human Protein Atlas (HPA). The relationship between clinicopathological features and GJA1 expression was analyzed by the chi-squared test and the logistic regression. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were used to assessing the effect of GJA1 expression on survival. Gene set enrichment analysis (GSEA) was used to screen the signaling pathways regulated by GJA1. Immune Cell Abundance Identifier (ImmuCellAI) was chosen to analyze the immune cells affected by GJA1. The expression of GJA1 in CC was significantly lower than that in normal tissues based on the GEPIA, GEO datasets, and HPA. Both the chi-squared test and the logistic regression showed that high-GJA1 expression was significantly correlated with keratinization, hormone use, tumor size, and FIGO stage. The Kaplan-Meier curves suggested that high-GJA1 expression could indicate poor prognosis (p = 0.0058). Multivariate analysis showed that high-GJA1 expression was an independent predictor of poor overall survival (HR, 4.084; 95% CI, 1.354-12.320; p = 0.013). GSEA showed many cancer-related pathways, such as the p53 signaling pathway and the Wnt signaling pathway, were enriched in the high-GJA1-expression group. Immune cell abundance analysis revealed that the abundance of CD8 naive, DC, and neutrophil was significantly increased in the high-GJA1-expression group. In conclusion, GJA1 can be regarded as a potential prognostic marker of poor survival and therapeutic target in CC. Moreover, many cancer-related pathways may be the critical pathways regulated by GJA1. Furthermore, GJA1 can affect the abundance of immune cells.

Figure 1

The expression of GJA1 and its association with clinicopathological parameters based on TCGA data: (a) histology type; (b) FIGO stage of all CC patients; (c) impact of GJA1 expression on OS in all CC patients; (d) FIGO stage of SCC patients; (e) impact of GJA1 expression on OS in all SCC patients; (f) impact of GJA1 expression on OS in patients with FIGO stage ≤ IIA2; (g) impact of GJA1 expression on OS in patients with FIGO stage ≥ IIB. TCGA: The Cancer Genome Atlas; FIGO: the International Federation of Gynecology and Obstetrics; CC: cervical cancer; OS: overall survival; SCC: squamous cell carcinoma; ACC: adenomas and adenocarcinomas; GJA1: gap junction protein alpha 1; ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001.

Figure 2

Forest plot for the multivariate Cox proportional hazard regression model. High-GJA1 expression was an independent predictor of poor survival rate (HR, 4.084; 95% CI, 1.354-12.320; p = 0.013). GJA1: Gap Junction Protein Alpha 1; HR: hazard ratio; CI: confidence interval; ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001.

Figure 3

A merged enrichment plot from gene set enrichment analysis (GSEA) including enrichment score and gene sets. 14 cancer-related pathways are shown here.

Figure 4

Immune cell abundance analysis between the low-GJA1-expression group and the high-GJA1-expression group. ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001.