Background: LAT1/4F2hc heterodimeric complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Although it has been shown that LAT1/4F2hc is highly expressed in a variety of human tumors including gliomas, and LAT1 over-expression is associated with glioma grade and poor prognosis of glioma patients, the precise tissue location of LAT1/4F2hc in gliomas and the precise role of LAT1/4F2hc in glioma biological features remain unclear. Methods: In the current study, the expressions of LAT1, 4F2hc, CD34 and Ki-67 were investigated by immunohistochemistry in 62 cases of human brain glioma; LAT1/4F2hc expression level, Ki-67 labeling index (Ki-67 LI) and microvessel density (MVD) were measured semi-quantitatively; and the correlation of LAT1/4F2hc expression with histopathological features, Ki-67 LI and MVD in gliomas was further analyzed. Results: The results showed that both LAT1 and 4F2hc were expressed in all examined specimens. LAT1 but 4F2hc expression levels significantly correlated with the pathological grade and both expression levels significantly correlated with Ki-67 LI of gliomas. We also demonstrated that both LAT1 and 4F2hc immunoreactivity were observed in tumor cells as well as vascular endothelia; furthermore, the LAT1 expression level was markedly associated with glioma MVD as well. Conclusion: LAT1/4F2hc over-expression is closely correlates with the malignant phenotype and proliferation of gliomas, and LAT1 was associates with glioma angiogenesis. LAT1/4F2hc, especially LAT1, may become a novel potential molecular target for glioma biological therapy.

Glioma is an aggressive brain tumor characterized by its high invasiveness, which complicates prognosis and contributes to patient resistance against various treatment options. The HOMER family, consisting of HOMER1, HOMER2, and HOMER3, has been implicated in various cancers, yet their specific roles in glioma remain inadequately understood. This study conducted a comprehensive pan-cancer analysis to evaluate the expression profiles of HOMER family members across different tumor types, utilizing data from public databases such as TCGA and GTEx. Our findings indicate significant dysregulation of HOMER1, HOMER2, and HOMER3 in multiple cancers, with HOMER3 emerging as a potential prognostic biomarker, particularly for lower-grade glioma. Elevated expression levels of HOMER3 were associated with shorter overall survival and disease-specific survival in LGG patients, supported by Cox regression analysis that confirmed HOMER3 as an independent prognostic factor. Furthermore, HOMER3 expression correlated positively with advanced clinical stages and key tumor markers. To elucidate the mechanisms behind HOMER3 dysregulation, we identified ELK4 as a transcription factor that binds to the HOMER3 promoter, promoting its expression in glioma cells. Functional assays demonstrated that silencing HOMER3 significantly reduced glioma cell proliferation and metastatic potential in vitro and in vivo, highlighting its oncogenic role. Additionally, HOMER3 was found to influence the Wnt/β-catenin/EMT signaling pathway, with knockdown resulting in altered expression of critical EMT markers. Collectively, our results indicated that HOMER3 plays a crucial role in glioma progression and metastasis, underscoring its potential as a therapeutic target and prognostic biomarker in glioma management.

Mitochondrial dysfunction has emerged as a critical factor in the progression and prognosis of low-grade glioma (LGG). In this study, we explored the role of mitochondrial-related genes through consensus clustering analysis using multi-omics data from the TCGA, CGGA, and other independent datasets. Patients were categorized into three clusters (Cluster A, B, and C), with Cluster B consistently associated with poorer prognosis. Mutation landscape analysis revealed distinct genetic alterations and copy number variations among clusters, particularly in Cluster B, which exhibited unique genetic signatures. Immune infiltration analysis showed that Cluster B had higher expression levels of immune checkpoint genes, stronger immune evasion activity, and greater immune cell infiltration, suggesting an immunosuppressive tumor microenvironment. Furthermore, we identified mitochondrial-related prognostic markers and developed a MITscore based on gene expression patterns, which stratified patients into high- and low-risk groups. High MITscore groups displayed stronger stemness characteristics, poorer survival outcomes, and differential responses to chemotherapy and immunotherapy. Cross-validation with drug sensitivity and immunotherapy cohorts indicated that high MITscore patients were more sensitive to certain chemotherapeutic agents and responded better to immunotherapy. Finally, using the SRGA method, we identified novel biomarkers (KDR, LRRK2, SQSTM1) closely associated with mitochondrial function, which may serve as potential targets for therapeutic intervention. These findings highlight the critical role of mitochondrial dysfunction in LGG prognosis, tumor microenvironment regulation, and treatment response, providing new avenues for precision oncology.