NRG1 promotes tumorigenesis and metastasis and afatinib treatment efficiency is enhanced by NRG1 inhibition in esophageal squamous cell carcinoma

Abstract

Abstract Background Esophageal squamous cell carcinoma (ESCC) is a highly aggressive cancer characterized by significant heterogeneity in incidence and outcomes. Neuregulin 1 (NRG1) plays a crucial role in the growth and development of multiple organ systems. While dysregulation of NRG1 is involved in the progression of multiple cancers, its specific role and contribution to the aggressiveness of ESCC remain unclear. This study aims to investigate the functions and molecular mechanisms of NRG1 in ESCC, as well as explore potential treatment strategies for ESCC cases with NRG1 overexpression. Methods We examined the expression levels of NRG1 in esophageal cancer and analyzed its correlation with gene copy number amplification and DNA methylation regulation. Various cellular and molecular assays were conducted to elucidate the functional role of NRG1 in ESCC. Additionally, the signaling pathways associated with NRG1 were investigated. Furthermore, we evaluated the efficacy of afatinib in ESCC with NRG1 overexpression, as well as the combined approach of NRG1 down-regulation and afatinib treatment. Results Our findings revealed that NRG1 was upregulated in esophageal cancer, showing a correlation with gene copy number amplification but not DNA methylation regulation. NRG1 was found to promote cell proliferation, migration, inhibit apoptosis, and accelerate tumorigenesis and metastasis in ESCC. Moreover, we discovered that NRG1 activated the NF-κB/MMP9 signaling pathway via the HER3-HER2/MAPK/PI3K pathway, contributing to the metastatic phenotype observed in ESCC. Finally, we demonstrated that afatinib effectively inhibited ESCC with NRG1 overexpression, and the combination of NRG1 down-regulation and afatinib treatment exhibited a more efficient strategy. Conclusions Our data strongly support the conclusion that NRG1 plays a crucial role in tumorigenesis and metastasis of ESCC, suggesting its potential as a novel biomarker for ESCC treatment.