High expression of interleukin-enhancer binding factor 3 predicts poor prognosis in patients with lung adenocarcinoma

Abstract

Interleukin-enhancer binding factor 3 (ILF3) is a double-stranded RNA-binding protein that has been reported to contribute to the occurrence and progression of various malignant tumors. The aim of the present study was to evaluate the prognostic value of ILF3 and to apply this knowledge to avoid excessive medical treatment in patients with lung adenocarcinoma (LUAD). ILF3 expression in a discovery set consisting of tumor and peri-tumor tissue microarrays was analyzed using immunohistochemical methods. The mRNA level of ILF3 was subsequently analyzed in a validation set downloaded from The Cancer Genome Atlas. The Kaplan-Meier method, univariate and multivariate Cox analyses, decision curve analysis and nomogram models were used to evaluate the prognostic value of ILF3. ILF3 expression was upregulated in tumor tissues compared with peri-tumor tissues and was negatively associated with the overall survival time of patients with LUAD in the discovery and validation sets. Moreover, ILF3 expression was used for risk stratification in patients with tumor-node-metastasis stages II-IV and poor-to-moderate tumor differentiation. ILF3 expression was identified as an independent predictor of adverse prognosis for patients with LUAD in the discovery and validation sets. Finally, nomogram models for the 3- and 5 year survival time of patients with LUAD revealed that ILF3 expression may be used to improve the predictive accuracy of the prognosis and to avoid excessive medical treatment for certain patients with the disease. Overall, the data obtained in the current study revealed that high ILF3 expression was associated with poor prognosis, and demonstrated that ILF3, as a potential independent risk factor, may improve the hierarchical postoperative management of patients with LUAD.

Keywords: interleukin-enhancer binding factor 3; lung adenocarcinoma; overall survival; prognosis; risk factor.

Figure 1.

Expression level of ILF3 in LUAD and normal tissues. (A) Representative images of ILF3 staining captured at ×40 (top) and ×400 (bottom) magnification. Scale bars, 500 µm (top) and 50 µm (bottom). (B) ILF3 staining intensity in tumor and peri-tumor tissues in the discovery set. (C) ILF3 mRNA levels in tumor and peri-tumor tissues in the TCGA validation set. ILF3, interleukin-enhancer binding factor 3; LUAD, lung adenocarcinoma; TCGA, The Cancer Genome Atlas; IHC, immunohistochemistry.

Figure 2.

Kaplan-Meier survival plots in patients with lung adenocarcinoma. Kaplan-Meier survival plots for the (A) discovery and (B) validation sets stratified by the tumor-node-metastasis stage. Kaplan-Meier survival plots for the (C) discovery and (D) validation sets stratified by ILF3 expression. ILF3, interleukin-enhancer binding factor 3.

Figure 3.

Subgroup analysis of the association between ILF3 expression and the overall survival time of patients with different TNM stages. Representation of the survival in the TNM (A) stage I and (B) stages II–IV subgroups in the discovery set stratified by ILF3 expression (high and low). (C) Forest plot based on ILF3 expression in the discovery set. Representation of the survival time in the TNM (D) stage I and (E) stages II–IV patient subgroups in the validation set stratified by ILF3 expression (high and low). (F) Forest plot based on ILF3 expression in the validation set. ILF3, interleukin-enhancer binding factor 3; TNM, tumor-node-metastasis; HR, hazard ratio; CI, confidence interval.

Figure 4.

Subgroup analysis of the association between ILF3 expression and the overall survival time of patients with different tumor differentiation. Representation of the survival time of patients in the discovery set with (A) well, (B) moderate and (C) poor tumor differentiation stratified by ILF3 expression (high and low). (D) Forest plot based on ILF3 expression in the discovery set. ILF3, interleukin-enhancer binding factor 3; HR, hazard ratio; CI, confidence interval.

Figure 5.

Forest plot based on ILF3 expression and other risk factors. In the discovery set, ILF3 expression (based on immunohistochemistry), tumor differentiation and TNM stage were identified as independent risk factors for OS time in patients with LUAD. In the validation set, ILF3 expression (based on the mRNA level), TNM stage and ethnicity were identified as independent risk factors for OS time in patients with LUAD. ILF3, interleukin-enhancer binding factor 3; TNM, tumor-node-metastasis; OS, overall survival; LUAD, lung adenocarcinoma; HR, hazard ratio; CI, confidence interval.

Figure 6.

Prognostic nomogram for patients with LUAD based on the discovery set data. (A) A prognostic nomogram integrating ILF3 expression (based on immunohistochemistry) and other risk factors (including smoking status, tumor differentiation and TNM stage) was generated to predict the clinical outcome of patients with LUAD. Calibration curves of the prognostic nomogram for the (B) 3- and (C) 5 year probability of survival time are presented. The red line represents an ideal model, and the vertical bars represent the 95% confidence interval. An ideal model suggests that the predicted outcome from the nomogram is completely identical to that of the actual observed outcome and it characterized by sensitivity 100%, specificity 100% and veracity 100%. LUAD, lung adenocarcinoma; ILF3, interleukin-enhancer binding factor 3; TNM, tumor-node-metastasis.

Figure 7.

Prognostic nomogram for patients with LUAD based on the validation set data. (A) A prognostic nomogram integrating ILF3 expression (based on the mRNA level) and other risk factors (including smoking status, ethnicity, age, gender and TNM stage) was generated to predict the clinical outcome of patients with LUAD. Calibration curves of the prognostic nomogram for the (B) 3- and (C) 5 year probability of survival time are presented. The lines on the top of (B) and (C) represent the distribution of patients. The red line represents an ideal model, and vertical bars represent the 95% confidence interval. LUAD, lung adenocarcinoma; ILF3, interleukin-enhancer binding factor 3; TNM, tumor-node-metastasis.