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.
Highlights
Cervical cancer (CC) is the fourth most common cancer in females, with 570,000 new cases and 311,000 deaths estimated for 2018 worldwide [1]
Gene Expression Profiling Interactive Analysis (GEPIA) was used to explore the mRNA expression levels of Gap Junction Protein Alpha 1 (GJA1) in CC and normal tissues, showing that GJA1 expression is significantly decreased in CC tissues (Figure S1A)
The results showed that tumor size (HR, 6.181; 95% confidence interval (CI), 1.219-31.334; p = 0:028), lymphovascular invasion (HR, 5.910; 95% CI, 1.124-31.059; p = 0:036), and the high-GJA1 expression (HR, 4.084; 95% CI, 1.354-12.320; p = 0:013) were the important independent predictors of poor overall survival of CC (Figure 2 and Table 4)
Summary
Cervical cancer (CC) is the fourth most common cancer in females, with 570,000 new cases and 311,000 deaths estimated for 2018 worldwide [1]. The vast majority of CC is in sub-Saharan Africa and South-Eastern Asia, and there were 98,900 new cases and 30,500 deaths for 2015 in China [1, 2]. The incidence and mortality rate of cervical declined due to vaccination, screening, and the control of precancerous lesions, it is even higher in some rural areas in China with the characteristics of young age (peak 45-49) and late stage [3,4,5]. Patients with early-stage CC (stages I to IIA) are mainly treated with surgery, whereas those with late-stage CC (stages IIB to IV) are treated with chemoradiotherapy [6]. It is crucial to identify sensitive and specific biomarkers that could predict CC prognosis and serve as a target for CC treatment
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