Heparin binding epidermal growth factor-like growth factor is a prognostic marker correlated with levels of macrophages infiltrated in lung adenocarcinoma

• Published in: Frontiers in oncology 2022-11, Vol.12, p.963896-963896
• Main Authors: Van Hiep, Nguyen, Sun, Wei-Lun, Feng, Po-Hao, Lin, Cheng-Wei, Chen, Kuan-Yuan, Luo, Ching-Shan, Dung, Le Ngoc, Van Quyet, Hoang, Wu, Sheng-Ming, Lee, Kang-Yun
• Format: Article
• Language: English
• Subjects: bioinformatics; biomarker; heparin-binding EGF-like growth factor (HBEGF); immune infiltration; macrophage chemotaxis; non-small cell lung cancer; Oncology
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2022.963896

The interactions between tumor cells and the host immune system play a crucial role in lung cancer progression and resistance to treatment. The alterations of EGFR signaling have the potential to produce an ineffective tumor-associated immune microenvironment by upregulating a series of immune suppressors, including inhibitory immune checkpoints, immunosuppressive cells, and cytokines. Elevated Heparin-binding EGF-like growth factor (HB-EGF) expression, one EGFR ligand correlated with higher histology grading, worse patient prognosis, and lower overall survival rate, acts as a chemotactic factor. However, the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the accumulation of immune cells in the tumor microenvironment remains unclear. The clinical association of HB-EGF expression in lung cancer was examined using the Gene Expression Omnibus (GEO) repository. HB-EGF expression in different cell types was determined using single-cell RNA sequencing (scRNA-seq) dataset. The correlation between HB-EGF expression and cancer-immune infiltrated cells was investigated by performing TIMER and ClueGo pathways analysis from TCGA database. The chemotaxis of HB-EGF and macrophage infiltration was investigated using migration and immunohistochemical staining. The high HB-EGF expression was significantly correlated with poor overall survival in patients with lung adenocarcinoma (LUAD) but not lung squamous cell carcinoma (LUSC). Moreover, HB-EGF expression was correlated with the infiltration of monocytes, macrophages, neutrophils, and dendritic cells in LUAD but not in LUSC. Analysis of scRNA-seq data revealed high HB-EGF expression in lung cancer cells and myeloid cells. Results from the pathway analysis and cell-based experiment indicated that elevated HB-EGF expression was associated with the presence of macrophage and lung cancer cell migration. HB-EGF was highly expressed in tumors and correlated with M2 macrophage infiltration in LUAD. HB-EGF is a potential prognostic marker and therapeutic target for lung cancer progression, particularly in LUAD.