Background: Pan-cancer analysis examines both the commonalities and heterogeneity among genomic and cellular alterations across numerous types of tumors. Pan-cancer analysis of gene expression, tumor mutational burden (TMB), microsatellite instability (MSI), and tumor immune microenvironment (TIME), and methylation becomes available based on the multi-omics data from The Cancer Genome Atlas Program (TCGA). Some online tools provide analysis of gene and protein expression, mutation, methylation, and survival for TCGA data. However, these online tools were either Uni-functional or were not able to perform analysis of user-defined functions. Therefore, we created the TCGAplot R package to facilitate perform pan-cancer analysis and visualization of the built-in multi-omic TCGA data. Results: TCGAplot provides several functions to perform pan-cancer paired/unpaired differential gene expression analysis, pan-cancer correlation analysis between gene expression and TMB, MSI, TIME, and promoter methylation. Functions for visualization include paired/unpaired boxplot, survival plot, ROC curve, heatmap, scatter, radar chart, and forest plot. Moreover, gene set based pan-cancer and tumor specific analyses were also available. Finally, all these built-in multi-omic data could be extracted for implementation for user-defined functions, making the pan-cancer analysis much more convenient.\ Conclusions: We developed an R-package for integrative pan-cancer analysis and visualization of TCGA multi-omics data. The source code and pre-built package are available at GitHub (https://github.com/tjhwangxiong/TCGAplot).

Immune infiltration of peripheral natural killer (NK) cells in the brain has been observed in Alzheimer’s disease (AD). Immunity-related genes (IRGs) play an essential role in immune infiltration; however, the expression of IRGs and possible regulatory mechanisms involved in AD remain unclear. The peripheral blood mononuclear cells (PBMCs) single-cell RNA (scRNA) sequencing data from patients with AD were analyzed and PBMCs obtained from the ImmPort database were screened for cluster marker genes. IRG activity was calculated using the AUCell package. A bulk sequencing dataset of AD brain tissues was analyzed to explore common IRGs between PBMCs and the brain. Relevant regulatory transcription factors (TFs) were identified from the Human TFDB database. The protein-protein interaction network of key TFs were generated using the STRING database. Eight clusters were identified, including memory CD4 T, NKT, NK, B, DC, CD8 T cells, and platelets. NK cells were significantly decreased in patients with AD, while CD4 T cells were increased. NK and DC cells exhibited the highest IRG activity. GO and KEGG analyses of the scRNA and bulk sequencing data showed that the DEGs focused on the immune response. Seventy common IRGs were found in both peripheral NK cells and the brain. Seventeen TFs were associated with IRG expression, and the PPI network indicated that STAT3, IRF1, and REL were the hub TFs. In conclusion, we propose that peripheral NK cells may infiltrate the brain and contribute to neuroinflammatory changes in AD through bioinformatic analysis of scRNA and bulk sequencing data. Moreover, STAT3 may be involved in the transcriptional regulation of IRGs in NK cells.

Background: Synaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs (circRNAs) are abundantly enriched in neural tissues, and aberrant expression of circRNAs precedes AD symptoms, significantly correlated with clinical dementia severity. However, the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood. Methods: Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice. RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3). The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining, co-immunoprecipitation and behavioral testing. Further, a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice. Results: circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice, which was mediated by METTL3-dependent N6-methyladenosine (m6A) modification. Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice. MiR-3968/UBE2K was validated as the downstream of circRIMS2. Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B. Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice. Conclusions: In conclusion, our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD.

Circular RNAs (circRNAs) are a class of single-stranded, covalent closed-loop RNAs with tissue-/development-specific expression patterns. circRNAs are stable and play oncogenic or tumor suppressive roles in various aspects of cancer, including tumorigenesis, proliferation, apoptosis, metastasis, invasion, chemo-therapeutic resistance, and prognosis. circRNAs act as miRNA/protein sponges, protein scaffold, or template for translation. Increasing evidence shows circRNAs contribute to cancer progression via modulating the expression or function of their host genes. In this review, we summarize the latest progress in the regulation of host genes by circRNAs in human cancer. The works on circRNAs mediated regulation of host genes enhance us to understand the interaction between circRNAs and their host genes in human cancer.