Significance of Runt-related transcription factor 1 and Notch1 expression in non-small-cell lung cancer: involvement in epithelial-mesenchymal transition and epidermal growth factor receptor-tyrosine kinase inhibitor therapy resistance

Abstract

Objective One of the main obstacles to treating patients with non-small-cell lung cancers (NSCLC) is the emergence of drug resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Aim To investigate the prognostic relevance of Runt-related transcription factor 1 (RUNX1) and Notch1 in NSCLC and to evaluate their potential involvement in induction of epithelial-mesenchymal transition and resistance to EGFR-TKI therapy. Materials and methods Immunohistochemical study of RUNX1, Notch1, E-cadherin, and hypoxia-inducible factor 1α (HIF-1α) was conducted upon 83 cases diagnosed as NSCLC. The research was conducted in the departments of pathology, chest, and medical oncology of the Faculty of Medicine, Benha University. Results A significant relation was found between RUNX1 and sex (P=0.001), smoking history (P=0.002), and tumor grade (P=0.002). High RUNX1 expression was associated with poor OS and DFS (P=0.003 and 0.005), respectively. Cases with positive Notch1 expression were significantly associated with tumor grade (P=0.005) and tumor stage (P=0.024). A significant association was detected between Notch1 expression and poor OS and DFS (P=0.025 and 0.011), respectively. A statistically significant correlation was found between RUNX1 and Notch1 expressions (P=0.040). Moreover, high RUNX1 and positive Notch1 expressions were significantly associated with negative E-cadherin and positive HIF-1α expressions. Resistance against EGFR–TKI therapy was significantly associated with high RUNX1, positive Notch1, negative E-cadherin, and positive HIF-1α expressions, in EGFR-mutated cases. Conclusions RUNX1 and Notch1 may be involved in therapy resistance through the induction of epithelial–mesenchymal transition and may serve as prognostic markers in patients with NSCLC.

Keywords

• epidermal growth factor receptor–tyrosine kinase inhibitor; epithelial–mesenchymal transition; notch1; runt-related transcription factor1