Critical Reviews in Eukaryotic Gene Expression最新文献

The development and progression of atherosclerosis represent a chronic process involving complex molecular interactions. Therefore, identifying the potential hub genes and pathways contributing to coronary artery disease (CAD) development is essential for understanding its underlying molecular mechanisms. To this end, we performed transcriptome analysis of peripheral venous blood collected from 100 patients who were divided into four groups according to disease severity, including 27 patients in the atherosclerosis group, 22 patients in the stable angina group, 35 patients in the acute myocardial infarction group, and 16 controls. Weighted gene co-expression network analysis was performed using R programming. Significant module-trait correlations were identified according to module membership and genetic significance. Metascape was used for the functional enrichment of differentially expressed genes between groups, and the hub genes were identified via protein-protein interaction network analysis. The hub genes were further validated by analyzing Gene Expression Omnibus (GSE48060 and GSE141512) datasets. A total of 9,633 messenger ribonucleic acids were detected in three modules, among which the blue module was highly correlated with the Gensini score. The hub genes were significantly enriched in the myeloid leukocyte activation pathway, suggesting its important role in the progression of atherosclerosis. Among these genes, the Mediterranean fever gene (MEFV) may play a key role in the progression of atherosclerosis and CAD severity.

As a newly discovered mechanism of cell death, disulfidptosis is expected to help diagnose and treat bladder cancer patients. First, data obtained from public databases were analyzed using bioinformatics techniques. SVA packages were used to combine data from different databases to remove batch effects. Then, the differential analysis and COX regression analysis of ten disulfidptosis-related genes identified four prognostically relevant differentially expressed genes which were subjected to Lasso regression for further screening to obtain model-related genes and output model formulas. The predictive power of the prognostic model was verified and the immunohistochemistry of model-related genes was verified in the HPA database. Pathway enrichment analysis was performed to identify the mechanism of bladder cancer development and progression. The tumor microenvironment and immune cell infiltration of bladder cancer patients with different risk scores were analyzed to personalize treatment. Then, information from the IMvigor210 database was used to predict the responsiveness of different risk patients to immunotherapy. The oncoPredict package was used to predict the sensitivity of patients at different risk to chemotherapy drugs, and its results have some reference value for guiding clinical use. After confirming that our model could reliably predict the prognosis of bladder cancer patients, the risk scores were combined with clinical information to create a nomogram to accurately calculate the patient survival rate. A prognostic model containing three disulfidptosis-related genes (NDUFA11, RPN1, SLC3A2) was constructed. The functional enrichment analysis and immune-related analysis indicated patients in the high-risk group were candidates for immunotherapy. The results of drug susceptibility analysis can guide more accurate treatment for bladder cancer patients and the nomogram can accurately predict patient survival. NDUFA11, RPN1, and SLC3A2 are potential novel biomarkers for the diagnosis and treatment of bladder cancer. The comprehensive analysis of tumor immune profiles indicated that patients in the high-risk group are expected to benefit from immunotherapy.

Objective: To identify and evaluate the bioinformatics of microRNA (miRNA) biomarkers in triple-negative breast cancer.

Methods: The MDA-MB-231 cell line with stable and low expression of c-Myc was created, and the expression patterns of messenger RNA (mRNA) and miRNA were investigated by cluster analysis. The genes regulated by c-Myc were then screened by transcriptome sequencing and miRNA sequencing. The negative binomial distribution of the DESeq software package was used to test for and determine the differential expression of genes.

Results: In the c-Myc deletion group, 276 differently expressed mRNAs were screened out by transcriptome sequencing, of which 152 mRNAs were considerably upregulated and 124 were significantly downregulated in comparison to the control group. One-hundred-seventeen (117) differentially expressed miRNAs were found using miRNA sequencing, of which 47 showed a substantial upregulation and 70 a significant downregulation. According to the Miranda algorithm, 1803 mRNAs could be targeted by 117 differently expressed miRNAs. Comparing the two sets of data, a total of 5 miRNAs were differentially expressed after targeted binding with 21 mRNAs, which were subjected to GO and KEGG enrichment analysis. The genes regulated by c-Myc were mainly enriched in signaling pathways such as extracellular matrix receptors and Hippo.

Conclusion: Twenty-one target genes and five differential miRNAs in the mRNA-c-Myc-miRNA regulatory network are potential therapeutic targets for triple-negative breast cancer.

TPP1, as one of the telomere-protective protein complex, functions to maintain telomere stability. In this study, we found that TPP1 was significantly upregulated in esophageal cancer (EC). We found that the proliferation and migration ability were significantly inhibited, while the results of flow cytometry assay indicated that the growth was hindered in the G1 phase after TPP1 knockdown. However, the proliferative viability and migratory ability were reversed after TPP1 overexpression in EC cells. Then, we found a significant increase in β-galactosidase positivity following TPP1 knockdown and the opposite following TPP1 overexpression in EC cells. Furthermore, TPP1 knockdown increased DNA damage and upregulated expression of the γ-H2AXS139 in the cell nucleus. Correspondingly, DNA damage was reversed after TPP1 overexpression in EC cells. Similarly, we found that the expression of ATM/ATR pathway proteins were upregulated after TPP1 knockdown, while the expression of the above proteins was downregulated after TPP1 overexpression in EC cells. TPP1 knockdown significantly inhibited the growth of transplanted tumors and upregulated the expression of ATM/ATR pathway proteins in transplanted tissues, whereas TPP1 overexpression significantly promoted their proliferation and downregulated the expression of the above proteins in vivo. Strikingly, we found that TPP1 could reduce the chemosensitivity of EC cells to cisplatin, which may have a potential link to clinical chemoresistance. In conclusion, TPP1 regulates the DNA damage response through the ATM/ATR-p53 signaling pathway and chemoresistance and may be a new target for improving the efficacy of chemotherapy in the treatment of EC.

Higher-order genomic organization supports the activation of histone genes in response to cell cycle regulatory cues that epigenetically mediates stringent control of transcription at the G1/S-phase transition. Histone locus bodies (HLBs) are dynamic, non-membranous, phase-separated nuclear domains where the regulatory machinery for histone gene expression is organized and assembled to support spatiotemporal epigenetic control of histone genes. HLBs provide molecular hubs that support synthesis and processing of DNA replication-dependent histone mRNAs. These regulatory microenvironments support long-range genomic interactions among non-contiguous histone genes within a single topologically associating domain (TAD). HLBs respond to activation of the cyclin E/CDK2/NPAT/HINFP pathway at the G1/S transition. HINFP and its coactivator NPAT form a complex within HLBs that controls histone mRNA transcription to support histone protein synthesis and packaging of newly replicated DNA. Loss of HINFP compromises H4 gene expression and chromatin formation, which may result in DNA damage and impede cell cycle progression. HLBs provide a paradigm for higher-order genomic organization of a subnuclear domain that executes an obligatory cell cycle-controlled function in response to cyclin E/CDK2 signaling. Understanding the coordinately and spatiotemporally organized regulatory programs in focally defined nuclear domains provides insight into molecular infrastructure for responsiveness to cell signaling pathways that mediate biological control of growth, differentiation phenotype, and are compromised in cancer.

Recurrent miscarriage (RM) is a frustrating and complex pregnancy disorder and long noncoding RNAs (lncRNAs) modulate susceptibility to RM. This study expounded on the role of specificity protein 1 (SP1) in functions of chorionic trophoblast and decidual cells via regulating lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1). Chorionic villus tissues and decidual tissues of RM patients and normal pregnant women were collected. Real-time quantitative polymerase chain reaction and Western blotting revealed that SP1 and NEAT1 were downregulated in trophoblast and decidual tissues of RM patients, and the Pearson correlation analysis detected that they were positively correlated in expression level. Chorionic trophoblast and decidual cells of RM patients were isolated and intervened by vectors over-expressing SP1 or NEAT1 siRNAs. Thereafter, the cell counting kit-8, Transwell, flow cytometry assays detected that SP1 overexpression accelerated trophoblast cell proliferation, invasion, and migration, meanwhile, enhancing decidual cell proliferation while repressed apoptosis. Next, the dual-luciferase and Chromatin immunoprecipitation assays showed that SP1 bound to the NEAT1 promoter region and further activated NEAT1 transcription. Silencing NEAT1 reversed the efforts of SP1 overexpression on the functions of trophoblast and decidual cells. Overall, SP1 activated NEAT1 transcription, accelerating trophoblast cell proliferation, invasion, and migration and mitigating decidual cell apoptosis.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult to treat of all malignancies. Multimodality regimens provide only short-term symptomatic improvement with minor impact on survival, underscoring the urgent need for novel therapeutics and treatment strategies for PDAC. We screened out the highly expressed gene LAMC2 in PDAC tissues through the GEO online database, and further demonstrated that it is related to the poor prognosis of PDAC patients. Next, we investigated the effect of LAMC2 in the development and metastasis of PDAC by silencing LAMC2 expression in PDAC cells. The results showed that silencing of LAMC2 inhibited the proliferation, invasion and metastasis, and promoted apoptosis of PDAC cells, silencing of LAMC2 also reversed the epithelial mesenchymal transition (EMT) and suppressed the activation of NF-κB signaling pathway. Our results identify LAMC2 as a pivotal regulator of PDAC malignant progression, and its overexpression is sufficient to confer the characteristically aggressive clinical features of this disease.

Diabetic nephropathy (DN) accompanied by cardiac fibrosis (CF) increases the mortality rate among people with diabetes. This study sought to explore the molecular mechanism of long non-coding RNA X inactive specific transcript (lncRNA XIST) in CF in DN mice. The animal model of DN was established by streptozocin (STZ). The levels of lncRNA XIST, microRNA (miR)-106a-5p, and RUNX family transcription factor 1 (RUNX1) were determined by quantitative real-time polymerase chain reaction (qRT-PCR), followed by biochemical analysis, hematoxylin & eosin and Masson staining, echocardiography, and quantification of collagen I, collagen III, α-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1) levels through qRT-PCR and Western blot assay. The subcellular localization of lncRNA XIST was analyzed by nuclear/cytoplasmic fractionation assay and the bindings of miR-106a-5p to lncRNA XIST and RUNX1 were confirmed by RNA immunoprecipitation and dual-luciferase assays. Functional rescue experiments were performed to validate the role of miR-106a-5p/RUNX1 in CF in DN mice. lncRNA XIST and RUNX1 were elevated while miR-106a-5p was decreased in STZ mice. lncRNA XIST inhibition reduced myocardial injury and collagen deposition, along with decreased levels of fasting blood glucose, serum creatinine, blood urea nitrogen, and urinary microalbumin, collagen I, collagen III, α-SMA, and TGF-β1. lncRNA XIST competitively bound to miR-106a-5p to promote RUNX1 transcription. miR-106a-5p downregulation or RUXN1 upregulation reversed the protective role of lncRNA XIST inhibition in STZ mice. lncRNA XIST competitively bound to miR-106a-5p to promote RUNX1 transcription, thereby aggravating renal dysfunction and CF in DN mice.

Osteosarcoma (OS) is the most representative primary bone tumour in children and teenagers. This study explored the regulatory effects of long noncoding RNA MIR503HG (MIR503HG) on the biological functions of OS cells, and further investigated the potential mechanism of MIR503HG function exertion by analyzing the microRNA-103a-3p (miR-103a-3p) in OS cells and tissues. The expression of MIR503HG was examined using reverse transcription-quantitative PCR. OS cell proliferation was assessed by CCK-8 assay. Transwell assay was used to evaluate the migration and invasion of OS cells. The interaction between MIR503HG and miR-103a-3p was detected using the Dual-luciferase reporter assay. Forty-six paired OS tissues were collected, and the expression and correlation of MIR503HG and miR-103a-3p were evaluated. The expression of MIR503HG were significantly decreased in both OS cells and tissues. Over-expression of MIR503HG inhibited OS cell proliferation, migration and invasion. miR-103a-3p was directly targeted by MIR503HG in OS cells, and mediated the inhibitory effects of MIR503HG on OS cell malignant behaviors. miR-103a-3p expression was upregulated in OS tissues, which was negatively correlated with MIR503HG expression levels. The expression of MIR503HG was associated with OS patients' tumor size, differentiation, distant metastasis and clinical stage. Decreased MIR503HG in OS tissues and cell lines served as a tumor suppressor by inhibiting OS cell malignant behaviors through sponging miR-103a-3p. The findings of this study may provide evidence for the development of novel therapeutic targets of OS.