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

Nguyen Van Hiep; Wei-Lun Sun; Po-Hao Feng; Cheng-Wei Lin; Kuan-Yuan Chen; Ching-Shan Luo; Le Ngoc Dung; Hoang Van Quyet; Sheng-Ming Wu; Kang-Yun Lee

doi:10.3389/fonc.2022.963896

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

Front Oncol. 2022 Nov 10:12:963896. doi: 10.3389/fonc.2022.963896. eCollection 2022.

Authors

Nguyen Van Hiep^{1

2

3}, Wei-Lun Sun^{4

5

6}, Po-Hao Feng^{4

5

6}, Cheng-Wei Lin^{1

6

7}, Kuan-Yuan Chen^{4

5

6

8}, Ching-Shan Luo^{1

4

6}, Le Ngoc Dung³, Hoang Van Quyet³, Sheng-Ming Wu^{4

5

6}, Kang-Yun Lee^{1

4

5

6

8}

Affiliations

¹ International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
² Oncology Center, Bai Chay Hospital, Quang Ninh, Ha Long, Vietnam.
³ Department of Thoracic and Neurological Surgery, Bai Chay Hospital, Quang Ninh, Ha Long, Vietnam.
⁴ Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
⁵ Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁶ TMU Research Center for Thoracic Medicine, Taipei Medical University, Taipei, Taiwan.
⁷ Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁸ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: HB-EGF is a potential prognostic marker and therapeutic target for lung cancer progression, particularly in LUAD.

Keywords: bioinformatics; biomarker; heparin-binding EGF-like growth factor (HBEGF); immune infiltration; macrophage chemotaxis; non-small cell lung cancer.