Significance of NotchScore and JAG1 in predicting prognosis and immune response of low-grade glioma.

Introduction: Low-grade glioma (LGG) is a prevalent malignant tumor in the intracranial region. Despite the advancements in treatment methods for this malignancy over the past decade, significant challenges still persist in the form of drug resistance and tumor recurrence. The Notch signaling pathway plays essential roles in many physiological processes as well as in cancer development. However, the significance of the pathway and family genes in LGG are poorly understood. Methods: We conducted gene expression profiling analysis using the TCGA dataset to investigate the gene set associated with the Notch signaling pathway. we have proposed a metric called "NotchScore" that quantifies the strength of the Notch signaling pathway and enables us to assess its significance in predicting prognosis and immune response in LGG. We downregulated JAG1 in low-grade gliomas to assess its influence on the proliferation and migration of these tumors. Ultimately, we determined the impact of the transcription factor VDR on the transcription of PDL1 through chip-seq data analysis. Results: Our findings indicate that tumors with a higher NotchScore, exhibit poorer prognosis, potentially due to their ability to evade the anti-tumor effects of immune cells by expressing immune checkpoints. Among the genes involved in the Notch signaling pathway, JAG1 has emerged as the most representative in terms of capturing the characteristics of both NotchScore and Notch pathways. The experimental results demonstrate that silencing JAG1 yielded a significant decrease in tumor cell proliferation in LGG cell lines. Our study revealed mechanisms by which tumors evade the immune system through the modulation of PDL1 transcription levels via the PI3K-Akt signaling pathway. Additionally, JAG1 potentially influences PDL1 in LGG by regulating the PI3K-Akt signaling pathway and the expression of the transcription factor VDR. Discussion: These findings contribute to our understanding of immune evasion by tumors in LGG. The insights gained from this research may have implications for the development of therapeutic interventions for LGG.

LncRNA AGPG Confers Endocrine Resistance in Breast Cancer by Promoting E2F1 Activity.

Resistance to endocrine therapy represents a major concern for patients with estrogen receptor α-positive (ERα+) breast cancer. Endocrine therapy resistance is commonly mediated by activated E2F signaling. A better understanding of the mechanisms governing E2F1 activity in resistant cells could reveal strategies for overcoming resistance. Here, we identified the long noncoding RNA (lncRNA) actin gamma 1 pseudogene 25 (AGPG) as a regulator of E2F1 activity in endocrine-resistant breast cancer. Expression of AGPG was increased in endocrine-resistant breast cancer cells, which was driven by epigenomic activation of an enhancer. AGPG was also abnormally upregulated in patient breast tumors, especially in the luminal B subtype, and high AGPG expression was associated with poor survival of patients with ERα+ breast cancer receiving endocrine therapy. The upregulation of AGPG mediated resistance to endocrine therapy and cyclin-dependent kinase 4/6 inhibition in breast cancer cells. Mechanistically, AGPG physically interacted with PURα, thus releasing E2F1 from PURα and leading to E2F1 signaling activation in ERα+ breast cancer cells. In patients with breast cancer, E2F1 target genes were positively and negatively correlated with expression of AGPG and PURα, respectively. Coadministration of chemically modified AGPG siRNA and tamoxifen strongly suppressed tumor growth in endocrine-resistant cell line-derived xenografts. Together, these results demonstrate that AGPG can drive endocrine therapy resistance and indicate that it is a promising biomarker and potential therapeutic target in breast cancer. SIGNIFICANCE: Blockade of formation of the PURα/E2F1 complex by lncRNA AGPG activates E2F1 and promotes endocrine resistance, providing potential strategies for combatting endocrine-resistant breast cancer.

A Comprehensive Analysis Revealing FBXW9 as a Potential Prognostic and Immunological Biomarker in Breast Cancer.

The WD40 repeat-containing F-box proteins (FBXWs) family belongs to three major classes of F-box proteins. Consistent with the function of other F-box proteins, FBXWs are E3 ubiquitin ligases to mediate protease-dependent protein degradation. However, the roles of several FBXWs remain elusive. In the present study, via integrative analysis of transcriptome profiles from The Cancer Genome Atlas (TCGA) datasets, we found that FBXW9 was upregulated in the majority of cancer types, including breast cancer. FBXW expression was correlated with the prognosis of patients with various types of cancers, especially for FBXW4, 5, 9, and 10. Moreover, FBXWs were associated with infiltration of immune cells, and expression of FBXW9 was associated with poor prognosis of patients receiving anti-PD1 therapy. We predicted several substrates of FBXW9, and TP53 was the hub gene in the list. Downregulation of FBXW9 increased the expression of p21, a target of TP53, in breast cancer cells. FBXW9 was also strongly correlated with cancer cell stemness, and genes correlated with FBXW9 were associated with several MYC activities according to gene enrichment analysis in breast cancer. Cell-based assays showed that silencing of FBXW9 inhibited cell proliferation and cell cycle progression in breast cancer cells. Our study highlights the potential role of FBXW9 as a biomarker and promising target for patients with breast cancer.

Integrative analyses of bulk microarray data to discover genes, pathways, and immune infiltration characteristics associated with targeting of Ewing sarcoma.

PURPOSE: To explore transcriptome and immunological features of patients with Ewing sarcoma (ES) using all publicly available microarray data. METHODS: Data of 479 ES tissues were integrated and normalized. Gene expression, immune infiltration, and cancer-specific pathways were analyzed. Genes of interest were knocked down, followed by cell proliferation and colony formation assays. RESULTS: Consistent with the previous reports of differential expressed genes (DEGs) in ES, our analysis identified CCND1, HMCN1, and NKX2-2 were among the most highly expressed, while TWNC1, MYBPC1, and CKM were among the lowest expressed genes. GO, KEGG, and GSEA enrichment analysis identified that the DEGs related to bone and muscle functioning, those that contributed to crucial cellular, and metabolism pathways such as actin binding, apoptosis, TCA cycle, and cell cycle were also significantly enriched. Immune infiltration analysis discovered that many T cell subsets including CD4T, CD8 T, and Gamma delta T cells were highly infiltrated, while monocytes and B cells were less infiltrated in tumors. A total of 138 genes were both significantly up-regulated in tumors and associated with decreased survival, while 38 significantly down-regulated genes were associated with increased survival, many of which were previously reported as oncogenes and tumor suppressors in ES and other cancers. Silencing of four newly identified top ranked up-regulated genes with decreased survivals in ES inhibited proliferation and colony formation of ES cells. CONCLUSION: This study may provide a clear representative transcriptome profile of ES, providing diagnostic biomarkers, pathways, and immune infiltrative characteristics targets for ES.