m7G‐related genes—NCBP2 and EIF4E3 determine immune contexture in head and neck squamous cell carcinoma by regulating CCL4/CCL5 expression

• Published in: Molecular carcinogenesis 2023-08, Vol.62 (8), p.1091-1106
• Main Authors: Xu, Xuhui, Zhao, Yue, Ying, Yukang, Zhu, Haoran, Luo, Jun, Mou, Tingchen, Zhang, Zhenxing
• Format: Article
• Language: English
• Subjects: Cancer immunotherapy; Cell Differentiation; Chemokine CCL5; Cluster Analysis; EIF4E3; Gene expression; Gene Expression Profiling; Genes; Head & neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - genetics; HNSCC; Humans; immune contexture; Immunomodulation; Immunoregulation; Immunotherapy; m7G modification; Metastases; Monocytes; NCBP2; Nomograms; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - genetics; Transcriptomes; Tumors; Western blotting
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.23548

Aberrant N7‐methylguanosine (m7G) levels closely correlate with tumor genesis and progression. NCBP2 and EIF4E3 are two important m7G‐related cap‐binding genes. This study aimed to identify the relationship between the EIF4E3/NCBP2 function and immunological characteristics of head and neck squamous cell carcinoma (HNSCC). Hierarchical clustering was employed in classifying HNSCC patients into two groups based on the expressions of NCBP2 and EIF4E3. The differentially expressed genes were identified between the two groups, and GO functional enrichment was subsequently performed. Weighted gene co‐expression network analysis was conducted to identify the hub genes related to EIF4E3/NCBP2 expression and immunity. The differential infiltration of immune cells and the response to immunotherapy were compared between the two groups. Single‐cell sequence and trajectory analyses were performed to predict cell differentiation and display the expression of EIF4E3/NCBP2 in each state. In addition, quantitative real‐time PCR, spatial transcriptome analysis, transwell assay, and western blotting were conducted to verify the biological function of EIF4E3/NCBP2. Here, group A showed a higher EIF4E3 expression and a lower NCBP2 expression, which had higher immune scores, proportion of most immune cells, immune activities, expression of immunomodulatory targets, and a better response to cancer immunotherapy. Besides, 56 hub molecules with notable immune regulation significance were identified. A risk model containing 17 hub genes and a prognostic nomogram was successfully established. Moreover, HNSCC tissues had a lower EIF4E3 expression and a higher NCBP2 expression than normal tissues. NCBP2 and EIF4E3 played a vital role in the differentiation of monocytes. Furthermore, the expression of CCL4/CCL5 can be regulated via EIF4E3 overexpression and NCBP2 knockdown. Collectively, NCBP2 and EIF4E3 can affect downstream gene expression, as well as immune contexture and response to immunotherapy, which could induce “cold‐to‐hot” tumor transformation in HNSCC patients.