Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response.
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ABSTRACT:
SUBMITTER: Andrysik Z
PROVIDER: S-EPMC7925689 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Breast cancer (BC) is a common malignant tumor in females around the world. While multimodality therapies exist, the mortality rate remains high. The hypoxic condition was one of the potent determinants in BC progression. The molecular mechanisms underpinning hypoxia and their association with BC can contribute to a better understanding of tailored therapies. In this study, two hypoxic induced BC transcriptomic cohorts (GSE27813 and GSE47533) were assessed from the GEO database. The P4HA1 gene was identified as a putative candidate and significantly regulated in hypoxic BC cells compared to normal BC cells at different time intervals (6 h, 9 h, 16 h, 32 h, and 48 h). In patients with Luminal (p < 1E-12), triple-negative subclasses (p = 1.35059E-10), Stage 1 (p = 8.8817E-16), lymph node N1 (p = 1.62436E-12), and in the 40-80 age group (p = 1.62447E-12), the expression of P4HA1 was closely associated with the clinical subtypes of BC. Furthermore, at the 10q22.1 chromosomal band, the P4HA1 gene displayed a high copy number elevation and was associated with a poor clinical regimen with overall survival, relapse-free survival, and distant metastases-free survival in BC patients. In addition, using BioGRID, the protein-protein interaction (PPI) network was built and the cellular metabolic processes, and hedgehog pathways are functionally enriched with GO and KEGG terms. This tentative result provides insight into the molecular function of the P4HA1 gene, which is likely to promote hypoxic-mediated carcinogenesis, which may favor early detection of BC and therapeutic stratification.
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Project description:Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte-colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma (PPARG) visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling-the major signaling receptor for collagen-as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between PPARG visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelial-to-mesenchymal transition-as in fibrosis and metastasis-and genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandin-endoperoxide synthase 2 (PTGS2) colorectal tumor expression is associated with a fibrotic signature in adipose-tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high PTGS2 expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose-tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted.See related spotlight by Colacino et al., p. 803.
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Project description:BackgroundHepatocellular carcinoma (HCC) was the sixth common malignancies characteristic with highly aggressive in the world. It was well established that tumor mutation burden (TMB) act as indicator of immunotherapeutic responsiveness in various tumors. However, the role of TMB in tumor immune microenvironment (TIME) is still obscure.MethodThe mutation data was analyzed by employing "maftools" package. Weighted gene co-expression network analysis (WGCNA) was implemented to determine candidate module and significant genes correlated with TMB value. Differential analysis was performed between different level of TMB subgroups employing R package "limma". Gene ontology (GO) enrichment analysis was implemented with "clusterProfiler", "enrichplot" and "ggplot2" packages. Then risk score signature was developed by systematical bioinformatics analyses. K-M survival curves and receiver operating characteristic (ROC) plot were further analyzed for prognostic validity. To depict comprehensive context of TIME, XCELL, TIMER, QUANTISEQ, MCPcounter, EPIC, CIBERSORT, and CIBERSORT-ABS algorithm were employed. Additionally, the potential role of risk score on immune checkpoint blockade (ICB) immunotherapy was further explored. The quantitative real-time polymerase chain reaction was performed to detect expression of HTRA3.ResultsTMB value was positively correlated with older age, male gender and early T status. A total of 75 intersection genes between TMB-related genes and differentially expressed genes (DEGs) were screened and enriched in extracellular matrix-relevant pathways. Risk score based on three hub genes significantly affected overall survival (OS) time, infiltration of immune cells, and ICB-related hub targets. The prognostic performance of risks score was validated in the external testing group. Risk-clinical nomogram was constructed for clinical application. HTRA3 was demonstrated to be a prognostic factor in HCC in further exploration. Finally, mutation of TP53 was correlated with risk score and do not interfere with risk score-based prognostic prediction.ConclusionCollectively, a comprehensive analysis of TMB might provide novel insights into mutation-driven mechanism of tumorigenesis further contribute to tailored immunotherapy and prognosis prediction of HCC.
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Project description:BackgroundExtrachromosomal circular DNAs (eccDNAs), a type of double-stranded DNAs (dsDNAs) that facilitate the activation of the DNA sensing machinery, have been implicated in the progression and prognosis of various diseases. While the roles of eccDNAs remain contentious, their significance in diffuse large B-cell lymphoma (DLBCL) has not been reported.MethodsCircular DNA sequencing (circle-seq) was used to demonstrate the expression profile of eccDNAs in DLBCL, and atomic force microscopy to validate the presence of eccDNAs. CCK-8 and scRNA-seq techniques were employed to uncover the activation of eccDNA in the STING pathway, leading to enhanced cell proliferation. Chemotherapeutic drugs were used to test the hypothesis that DNA damage induces the production of eccDNA, thereby activating the STING pathway independent of cGAS. GEO databases were used for verification of the prognosis of the eccDNA-related genes, and animal models were used to investigate the synergistic effects of DNA damage therapy in combination with STING inhibitors on anti-tumour responses.ResultsEccDNAs were widely expressed in DLBCL and associated with the prognosis of patients. Elevated abundance of eccDNAs promoted the progression of DLBCL. Chemotherapeutic drugs-induced DNA damage triggered the generation of eccDNAs, resulting in the activation of the STING signalling in a cGAS-independent manner. Moreover, inhibition of STING exerted a synergistic anti-tumour effect with cisplatin.ConclusionsEccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. This finding offers a rational therapeutic strategy combining chemotherapy with targeting STING.HighlightsEccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. The combined treatment of chemotherapeutic drugs with STING inhibitor significantly delayed the tumor progression, providing new insights into the therapeutic strategy for patients with DLBCL, particularly the relapsed and/or refractory (R/R) ones.
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Project description:Colon adenocarcinoma (COAD) is one of the most frequent malignant lesions of the digestive system in humans, with an insidious onset. At the time of diagnosis, most of them have developed to the middle and late stages, and cancer cells have metastasized, and the prognosis is poor. Treatment options for progressive COAD are limited, and despite the promise of immunotherapy, immunotherapy response rates are low. The assembly and disaggregation of focal adhesion are critical for the directional migration of tumor cells to different sites, and it is unclear whether focal adhesion-related genes are involved in the development and prognosis of colon adenocarcinoma. This study aimed to investigate the role of focal adhesion genes in the occurrence and prognosis of COAD. We obtained datasets of COAD patients, including RNA-sequencing data and clinical information, from the TCGA and GEO databases (GSE17538 and GSE39582). Through CNMF clustering, two molecular subtypes with different expression patterns of focal adhesion genes were identified, and it was found that the molecular subtype with low expression of focal adhesion genes had better prognosis. Then the prediction signature was constructed by LASSO-Cox regression model, and the receiver operating characteristic (ROC) curve showed that the 4-gene signature had a good prediction effect on COAD 1-, 2-, and 3-year OS. Gene function enrichment analysis showed that the high-risk group was mainly enriched in immune and adhesion-related signaling pathways, suggesting that focal adhesion genes may affect the development and prognosis of COAD by regulating the immune microenvironment and tumor metastasis. The interaction between focal adhesion genes and immunity during the occurrence of COAD may help improve the response rate of immunotherapy, which also provides new ideas for the molecular mechanism and targeted therapy in COAD.
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Project description:Background Salt stress is one of the most destructive environmental factors limiting crop growth and development. MicroRNAs (miRNAs) are a class of conserved endogenous small non-coding RNAs, playing the crucial role in regulating salt response and tolerance in plants. However, the miRNAs in wild emmer wheat, especially the key and specific salt-responsive miRNAs are not well studied. Results Here, we performed small RNA, transcriptome, and degradome sequencing of both of salt-tolerance (ST) and salt-sensitive (SS) wild emmer genotypes to identify the miRNA-mRNA modules associating with salt tolerance. Totally, 775 miRNAs, including 361 conserved known miRNAs and 414 novel miRNAs were detected. Differential expression analysis identified 93 salt-responsive miRNAs under salt stress. Combined with RNA-seq and degradome sequencing analysis, 224 miRNA-mRNA modules displayed the complete opposite expression trends between ST and SS genotypes, most of which functionally enriched into ROS homeostasis maintaining, osmotic pressure modulating, and root growth and development. Finally, the qRT-PCR and a large-scale yeast functional screening were also performed to initially validate the expression pattern and function of candidate genes. Conclusions This study reported the key and specific miRNA-mRNA modules associated with salt tolerance in wild emmer, which lay the foundation for improving the salt tolerance in cultivated emmer and bread wheat through miRNA engineering approach. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-022-08945-3.
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