Stem signatures associating SOX2 antibody helps to define diagnosis and prognosis prediction with esophageal cancer

Abstract

Background: esophageal cancer is one of the deadliest diseases worldwide. Due to the ineffectual screening methods referring to early diagnosis, most people have lost their chance of radical resection when diagnosed with esophageal cancer. This aim of this study was designed to evaluate the latent values of the stem signatures-associated autoantibodies (AABS) in predicting the early diagnosis, and particularly seeking the precise predictive outcomes with sensitive SOX2. We also studied the potential immunotherapeutic targets and prospective long-term prognosis predicators of esophageal cancer.

Methods: The serum concentrations of selective antibodies were quantitated by enzyme-linked immunosorbent assay (ELISA), and a total of 203 local cases were enrolled. The TCGA databases were used to analyse distinct expression patterns and prognostic values of related genes. The TIMER database was used to explore the signatures of immune cell infiltration in related genes. The TISIDB database was used to analyse the association between related genes and immune regulators.

Results: The stem signatures-associated with antibodies of TP53, PGP9.5, SOX2, and CAGE were highly expressed in esophageal cancer and were negatively correlated with the test group, the diagnostic sensitivity of P53, SOX2, PGP9.5 and CAGE reached to 54.3%, 56.5%, 80.4% and 47.8%, respectively, and the specificity reached 77.7%, 93.6%, 76.4% and 86.6%. Especially in stage I esophageal cancer, the diagnostic sensitivity of SOX2 reached 82.4% with a specificity of 85.4%, which demonstrated good value in early diagnosis.

Conclusions: The stem signatures-associated antibodies could be used as an effective indicator in early esophageal cancer diagnosis and could help to precisely predicate survival and prognosis.Key MessagesThe stem signatures-associated immune-antibodies could be used as effective indicators in early diagnosis of esophageal cancer and help to precisely predicate the survival and prognosis.The potential immunotherapeutic targets referring to esophageal cancer are screened and analysed, and the high sensitivity of SOX2 in detecting early esophageal cancer will yield early and effective treatments.

Keywords: SOX2; Stem cells signatures; early diagnosis; immune infiltration evaluation; oesophageal cancer.

Figure 1.

Different expression of SOX2 indicated diverse disease-free survival and overall survival expectations. Expression patterns of SOX2 in kinds of cancer were shown, and through TGCA database and heat map of genes, SOX2 is up-regulating expression in different tumour types, including esophageal, lung and ovarian cancer, especially in esophageal squamous carcinoma (A) and adenocarcinoma (B). The DFS and OS survival curves comparing patients with alteration (red) and without alteration (blue) referring to expression of SOX2 (C and D). Information on 10,953 patients and 10,967 samples were analysed through the TGCA Atlas database. We can know that cases with alternations have a lower disease free survival compared with cases without alternations (p = 0.0219, *p <.05), and cases with alternations have a much shorter overall survival compared with cases without alternations (p = 7.92e-6, *p<.05). Protein Atlas data were screened for SOX2 expression patterns (E). SOX2 upregulates the expression in different tumour types, including esophageal, head and neck, and lung squamous cancer.

Figure 2.

SOX2/Notch signalling phenotype in esophageal carcinoma. The OS and PFS survival curves comparing patients with esophageal adenocarcinoma (A) and esophageal squamous cell carcinoma (B) were plotted using Kaplan–Meier plotter analysis. (C–D) Different expression patterns of SOX2/Notch signalling phenotype in esophageal adenocarcinoma and esophageal squamous cell carcinoma were drafted, and the SOX2 expression patterns were much similar in either squamous carcinoma and adenocarcinoma. The overexpressed SOX2 was frequently occurred in either squamous carcinoma (E) and adenocarcinoma, especially in squamous esophageal carcinoma. (F) SOX2 expression level was significantly higher in squamous esophageal carcinoma than esophageal adenocarcinoma (G), and the SOX2-associated Notch signalling was co-activated (H–K). (I) The Notch1 signalling mRNA expression level was significantly higher in squamous esophageal carcinoma than esophageal adenocarcinoma. The Notch3 signalling mRNA expression level was significantly higher in squamous esophageal carcinoma than esophageal adenocarcinoma.

Figure 3.

Different kind of expression of SOX2 in different race groups. The OS (A) and PFS (B) survival curves comparing patients with Asian (red) and White (blue) were plotted using Kaplan–Meier plotter scribing. Different mRNAs levels of SOX2/Notch signalling phenotypes in Asian and White were analysed, and the mRNA overexpression of SOX2 (C) and Notch1 (D) signalling was significant both in Asian and White. (E) The mRNA expression of Notch3 signalling was significantly different between Asian and White. (F) Asian patients always exhibited higher SOX2 alternation frequency than other patients. (G–H) Higher SOX2 alternation frequency was always significantly associated with higher mutation burden, and lower expression intensity.

Figure 4.

Stem signatures associated antibodies in immune response prediction diagnosis of esophageal cancer. The different levels of immune cell infiltration in stem signatures associated antibodies were analysed, including Purity, B Cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, dendritic cell expressions in esophageal cancer through TIMER database. (A) P53 was associated with Purity (r = 0.156, p = 3.64e-02), B Cell (r= −0.1, p = 1.84e-01), CD8 + Tcell (r= −0.144, p = 5.38e-02), CD4 + Tcell(r = 0.093, p = 2.16e-01), Macrophage (r= −0.013, p = 8.65e-01), Neutrophil (r= −0.166, p = 2.56e-02), Dendritic Cell (r = 0.064, p = 3.93e-01). (B) SOX2 was significantly associated with Purity (r= −0.04, p = 5.97e-01), B Cell (r= −0.07, p = 9.22e-01), CD8 + Tcell (r= −0.001, p = 9.91e-01), CD4 + T cell (r= −0.084, p= p = 2.65e-01), Macrophage (r = 0.065, p = 3.88e-01), Neutrophil (r= −0.184, p = 1.35e-02), Dendritic Cell (r= −0.195, p = 8.81e-03). (C) PGP9.5 was significantly associated with Purity (r = 0.077, p = 3.02e-01), B Cell (r= −0.118, p = 1.16e-01), CD8 + Tcell (r= −0.248, p = 7.79e-04),CD4 + Tcell (r= −0.042, p = 5.77e-01), Macrophage (r= −0.06, p = 4.26e-01), Neutrophil (r= −0.095, p = 2.03e-01), Dendritic Cell (r = 0.079, p = 2.94e-01). (D) CAGE was significantly associated with Purity (r = 0.071, p = 3.41e-01), B Cell (r = 0.075, p = 3.20e-01), CD8 + Tcell (r= −0.005, p = 9.43e-01), CD4 + T cell (r= −0.141, p = 6.01e-02), Macrophage(r = 0.018, p = 8.12e-01), Neutrophil (r= −0.166, p = 2.63e-02), Dendritic Cell (r= −0.253, p = 6.24e-04). The results indicated that SOX2, P53, and PGP9.5 were negatively correlated to Immuno-inhibitors (E), immuno-stimulators (F), and MHC molecules (G).

Figure 5.

Diagnosis of esophageal cancer patients with Stem signatures associated antibodies. (A) ROC curves of four AAbs distinguishing esophageal cancer group from control groups. (B) ROC curves of four AAbs distinguishing esophageal squamous cell carcinoma cancer group from control groups (benign lesions and healthy people) (B).