Identification of Implications of Angiogenesis and m6A Modification on Immunosuppression and Therapeutic Sensitivity in Low-Grade Glioma by Network Computational Analysis of Subtypes and Signatures

Abstract

Angiogenesis is a complex process in the immunosuppressed low-grade gliomas (LGG) microenvironment and is regulated by multiple factors. N6-methyladenosine (m6A), modified by the m6A modification regulators (“writers” “readers” and “erasers”), can drive LGG formation. In the hypoxic environment of intracranial tumor immune microenvironment (TIME), m6A modifications in glioma stem cells are predominantly distributed around neovascularization and synergize with complex perivascular pathological ecology to mediate the immunosuppressive phenotype of TIME. The exact mechanism of this phenomenon remains unknown. Herein, we elucidated the relevance of the angiogenesis-related genes (ARGs) and m6A regulators (MAGs) and their influencing mechanism from a macro perspective. Based on the expression pattern of MAGs, we divided patients with LGG into two robust categories via consensus clustering, and further annotated the malignant related mechanisms and corresponding targeted agents. The two subgroups (CL1, CL2) demonstrated a significant correlation with prognosis and clinical-pathology features. Moreover, WGCNA has also uncovered the hub genes and related mechanisms of MAGs affecting clinical characters. Clustering analysis revealed a synergistic promoting effect of M6A and angiogenesis on immunosuppression. Based on the expression patterns of MAGs, we established a high-performance gene-signature (MASig). MASig revealed somatic mutational mechanisms by which MAGs affect the sensitivity to treatment in LGG patients. In conclusion, the MAGs were critical participants in the malignant process of LGG, with a vital potential in the prognosis stratification, prediction of outcome, and therapeutic sensitivity of LGG. Findings based on these strategies may facilitate the development of objective diagnosis and treatment systems to quantify patient survival and other outcomes, and in some cases, to identify potential unexplored targeted therapies.

YTHDF1 Attenuates TBI-Induced Brain-Gut Axis Dysfunction in Mice

“…An increasing number of studies have focused on the role of RNA m 6 A methylation in the development of various neurological diseases, such as Parkinson’s disease [ 23 ], Alzheimer’s disease [ 24 , 25 ], multiple sclerosis [ 26 ], tumours [ 27 , 28 , 29 ], epilepsy [ 30 ], and neuropsychiatric disorders [ 31 ]. However, to date, there is limited research focusing on the role of RNA m 6 A methylation in TBI and BGA.…”

The Comprehensive Analysis of m6A-Associated Anoikis Genes in Low-Grade Gliomas

“…This dynamic and reversible epigenetic modification affects the fate of RNA molecules and further regulates mammalian cell differentiation, immunity, and apoptosis. Studies have shown that the imbalance of m6A is involved in the development of gliomas [ 7 , 19 , 20 ]. M6A can regulate cell self-renewal, differentiation, invasion, and apoptosis by regulating gene expression.…”

“…Meanwhile, m6A modification in LGG is significantly associated with angiogenesis. Each of the 17 m6A regulators and 36 ARGs exhibited a significant self-positive correlation [ 20 ], and the researcher found that three m6a-lncRNAs, including ELOA-AS1, HOXB-AS1, and FLG-AS1, were closely related to the prognosis of LGG patients. Cancer cells can resist anoikis in several ways, such as by secreting growth factors, activating pro-survival signaling pathways, and altering integrin expression patterns [ 21 ].…”

The Potential Role of m6A in the Regulation of TBI-Induced BGA Dysfunction

“…Therefore, the abnormal expression of m 6 A-related proteins may lead to the development of various neurological diseases, such as PD [ 145 , 146 , 147 ], AD [ 148 , 149 , 150 , 151 , 152 ], MS [ 153 ], tumours [ 154 , 155 , 156 ], epilepsy [ 157 ], and neuropsychiatric disorders [ 158 ]. TBI, as one of the major diseases of CNS, often causes memory problems in humans [ 159 ].…”