Glioma is an invasive and highly diffuse brain tumor. Current standard treatment for glioma patients includes maximum safe surgical resection, simultaneous radiotherapy and temozolomide, and then adjuvant temozolomide. Glioma is still an incurable disease, the average OS after standard treatment is 12–15 months, and relapse is inevitable. Therefore, it is extremely important to explore new methods to improve the prognosis of glioma patients and improve the quality of life of patients. Research results in recent years have shown that the tumor microenvironment plays an important role in the occurrence and development of glioma. An in-depth understanding of the tumor microenvironment is beneficial to provide new immunotherapy for glioma patients to inhibit tumor development[40, 41]. In recent years, immune checkpoint inhibitors against members of the EGFR family of gliomas have been widely tested in clinical trials, opening up broad prospects for the treatment of gliomas[42, 43]. In this study, we analyzed the expression of EGFR family members in gliomas, the relationship with prognosis, and immune infiltration. It suggests that the EGFR family mRNA level is related to the poor prognosis of glioma. In addition, EGFR family mRNA levels are correlated with the abundance of tumor-infiltrating immune cells. Overall, our study provides new insights into the important role of the EGFR family in the assessment of glioma prognosis and immune infiltration.
The abnormal expression of the EGFR family in large number of human cancers has been studied, however the study of the EGFR family in gliomas is still uncertain[44, 45]. Here, in order to clarify the expression profile of the EGFR family in all grades of gliomas, by analyzing the glioma samples in the CGGA and TCGA data sets, we summarized the expression patterns and distribution of the EGFR family. We found that the expression of EGFR family in glioma has significant changes in mRNA levels. At the same time, the expression of EGFR family in various subtypes in gliomas is significantly different, suggesting that the expression of EGFR family is related to malignant phenotype and tumor progression. In addition, the EGFR family is significantly different in IDH-mutated gliomas, suggesting that IDH may be a regulator of the EGFR family.
After binding and activation, EGFR can form a dimer structure with other members. It preferentially binds to ERBB2 to form a stronger heterodimer. It initiates a series of cascade reactions through autophosphorylation, participates in cell signal transmission, and converts signals. It spreads into the nucleus and plays an important role in normal cell proliferation, differentiation and migration. EGFR gene amplification and overexpression can be seen in a variety of human malignancies, including non-small cell lung cancer, breast cancer, ovarian cancer, gastric cancer, and etc. Abnormal EGFR gene activation is closely related to tumor cell proliferation, angiogenesis, tumor invasion and migration, and inhibition of apoptosis.
ERBB2 forms a heterodimer with other members of the family, indirectly binds to the ligand, activates the tyrosine kinase in the intracellular segment, triggers downstream signal transduction, and the signal is transmitted to the nucleus through the intercellular substance, activating cell proliferation-related genes, thereby Promote cell mitosis, regulate cell proliferation, differentiation, migration and tumor formation[52, 53]. ERBB2 is overexpressed to varying degrees in various malignancies such as breast cancer, ovarian cancer, non-small cell lung cancer, gastric cancer, and etc..
ERBB3 / ERBB2 dimer is the most active ERBB dimer in ERBB dimer, which can activate PI3K/AKT Jak/Stat and other signaling pathways, regulate cell proliferation, differentiation, migration and other activities. ERBB3 is closely related to the occurrence and development of various tumors. Abnormal activation and overexpression of the HER3 gene can be seen in malignant tumors such as breast cancer, gastric cancer, ovarian cancer, prostate cancer, and etc..
After binding ERBB4 with ligands (neurodifferentiation factor heparin binding epidermal growth factor, etc.), it activates downstream PI3K/Akt Ras/Raf/MAPK signaling pathways through autophosphorylation, and mediates extracellular growth factor signaling through the intracellular kinase cascade Intracellular transmission, thereby regulating angiogenesis and cell growth, differentiation, proliferation and apoptosis.
In recent years, the importance of immune cell infiltration in tumors has gradually been recognized[64, 65]. Blocking immune checkpoints has become a promising cancer treatment. However, the relationship between the EGFR family and immune infiltration in gliomas has not been studied. In this paper, the timer database was used to analyze the relationship between EGFR family expression and immune penetration in gliomas. The expression of EGFR has a notably correlation with the level of B cell infiltration. ERBB2 expression was notably correlated with the level of macrophage infiltration. The expression of ERBB3 and ERBB4 was positively correlated with the level of CD4 + T cell infiltration. These correlations may suggest the potential mechanism of EGFR family to regulate immune cells of glioma. These findings indicate that the EGFR family plays a crucial role in the regulation of glioma immune cells.
In order to explore the potential mechanism of EGFR family involvement in glioma carcinogenesis, we constructed a PPI network and performed GO and KEGG analysis of the EGFR family on the basis of DAVID. The results showed that EGFR family interacting genes are mainly involved cell motility, which may affect integrin receptors and Rho family GTPases. Integrin receptors has been reported to interact with EGFR. Moreover, Rho family GTPases play an important role in the interaction between EGFR family and their interactors. In summary, the interaction between integrin receptors/Rho family GTPases and the EGFR family may become a new antitumor therapy strategy by regulating signaling pathway.