Algorithmic Annotation of Functional Roles for Components of 3,044 Human Molecular Pathways

Sorokin, Maxim; Borisov, Nicolas; Kuzmin, Denis; Gudkov, Alexander; Zolotovskaia, Marianna; Garazha, Andrew; Buzdin, Anton

doi:10.3389/fgene.2021.617059

Cited by 31 publications

(30 citation statements)

References 55 publications

(50 reference statements)

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“…Using the Mann–Whitney test, we performed a statistically significant overrepresentation test, which can be used to evaluate whether any ontology class or path has a nonrandomly distributed significance relative to the overall set of attributes. Dysregulated pathway-related HCC-specific genes were analyzed as described in a recent report article by Buzdin A et al 18 , the activation or inhibition of differentially regulated pathway were denoted by using the pathway activation levels (PALs). Pathway enrich score was calculated with GSVA and differential genes were analyzed by R package limma.…”

Section: Methodsmentioning

confidence: 99%

RNA-seq profiling reveals PBMC RNA as a potential biomarker for hepatocellular carcinoma

Han

Feng

et al. 2021

Sci Rep

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and has extremely high morbidity and mortality. Although many existing studies have focused on the identification of biomarkers, little information has been uncovered regarding the PBMC RNA profile of HCC. We attempted to create a profile throughout using expression of peripheral blood mononuclear cell (PBMC) RNA using RNA-seq technology and compared the transcriptome between HCC patients and healthy controls. Seventeen patients and 17 matched healthy controls were included in this study, and PBMC RNA was sequenced from all samples. Sequencing data were analyzed using bioinformatics tools, and quantitative reverse transcription PCR (qRT-PCR) was used for selected validation of DEGs. A total of 1,578 dysregulated genes were found in the PBMC samples, including 1,334 upregulated genes and 244 downregulated genes. GO enrichment and KEGG studies revealed that HCC is closely linked to differentially expressed genes (DEGs) implicated in the immune response. Expression of 6 selected genes (SELENBP1, SLC4A1, SLC26A8, HSPA8P4, CALM1, and RPL7p24) was confirmed by qRT-PCR, and higher sensitivity and specificity were obtained by ROC analysis of the 6 genes. CALM1 was found to gradually decrease as tumors enlarged. Nearly the opposite expression modes were obtained when compared to tumor sequencing data. Immune cell populations exhibited significant differences between HCC and controls. These findings suggest a potential biomarker for the diagnosis of HCC. This study provides new perspectives for liver cancer development and possible future successful clinical diagnosis.

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Section: Methodsmentioning

confidence: 99%

RNA-seq profiling reveals PBMC RNA as a potential biomarker for hepatocellular carcinoma

Han

Feng

et al. 2021

Sci Rep

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“…We then built PCA plot based on 1611 molecular pathway activation profiles [ 29 ], where pathway activation level (PAL) of a pathway is calculated using transcriptomic data ( Figure 1 B). PAL can take positive or negative values in the case of pathway up- or down-regulation, respectively, and positively reflects the extent of a pathway activation, and thus can be used as the quantitative characteristic of the interactome under study [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

“…Pathway activation levels (PALs) were established using Oncobox pathway analysis method [ 28 ] for 1611 molecular pathways containing 10 or more gene products extracted from the public databases [ 29 ] using the original software [ 29 ]. For PAL calculations, each sample expression profile was normalized on mean geometrical levels of gene expression for all samples in the dataset under investigation.…”

Section: Methodsmentioning

confidence: 99%

“…For each dataset under investigation we performed Cox survival analysis and extracted relevant differential genes [37]. To this end, for every gene we identified two respective patient groups by this gene expression levels: (i) patients with the expression level higher than 66th-percentile among all patients (in the top third), and (ii) patients We then built PCA plot based on 1611 molecular pathway activation profiles [29], where pathway activation level (PAL) of a pathway is calculated using transcriptomic data (Figure 1B). PAL can take positive or negative values in the case of pathway up-or downregulation, respectively, and positively reflects the extent of a pathway activation, and thus can be used as the quantitative characteristic of the interactome under study [36].…”

Section: Survival-linked Differential Gene Analysismentioning

confidence: 99%

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Large-Scale Transcriptomics-Driven Approach Revealed Overexpression of CRNDE as a Poor Survival Prognosis Biomarker in Glioblastoma

Sorokin

Raevskiy

Zottel

et al. 2021

Cancers

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Glioblastoma is the most common and malignant brain malignancy worldwide, with a 10-year survival of only 0.7%. Aggressive multimodal treatment is not enough to increase life expectancy and provide good quality of life for glioblastoma patients. In addition, despite decades of research, there are no established biomarkers for early disease diagnosis and monitoring of patient response to treatment. High throughput sequencing technologies allow for the identification of unique molecules from large clinically annotated datasets. Thus, the aim of our study was to identify significant molecular changes between short- and long-term glioblastoma survivors by transcriptome RNA sequencing profiling, followed by differential pathway-activation-level analysis. We used data from the publicly available repositories The Cancer Genome Atlas (TCGA; number of annotated cases = 135) and Chinese Glioma Genome Atlas (CGGA; number of annotated cases = 218), and experimental clinically annotated glioblastoma tissue samples from the Institute of Pathology, Faculty of Medicine in Ljubljana corresponding to 2–58 months overall survival (n = 16). We found one differential gene for long noncoding RNA CRNDE whose overexpression showed correlation to poor patient OS. Moreover, we identified overlapping sets of congruently regulated differential genes involved in cell growth, division, and migration, structure and dynamics of extracellular matrix, DNA methylation, and regulation through noncoding RNAs. Gene ontology analysis can provide additional information about the function of protein- and nonprotein-coding genes of interest and the processes in which they are involved. In the future, this can shape the design of more targeted therapeutic approaches.

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“…Pathway activation levels (PALs) were calculated with Oncobox Library ( Sorokin et al, 2021 ) with the default set of pathway databases. Comparison of PALs between ELOVL5 / IGBFP6 knockdown cells with control ones was done with Student’s t -test; Benjamini–Hochberg procedure was used to adjust p -values.…”

Section: Methodsmentioning

confidence: 99%

Effect of the Expression of ELOVL5 and IGFBP6 Genes on the Metastatic Potential of Breast Cancer Cells

et al. 2021

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Breast cancer (BC) is the leading cause of death from malignant neoplasms among women worldwide, and metastatic BC presents the biggest problems for treatment. Previously, it was shown that lower expression of ELOVL5 and IGFBP6 genes is associated with a higher risk of the formation of distant metastases in BC. In this work, we studied the change in phenotypical traits, as well as in the transcriptomic and proteomic profiles of BC cells as a result of the stable knockdown of ELOVL5 and IGFBP6 genes. The knockdown of ELOVL5 and IGFBP6 genes was found to lead to a strong increase in the expression of the matrix metalloproteinase (MMP) MMP1. These results were in good agreement with the correlation analysis of gene expression in tumor samples from patients and were additionally confirmed by zymography. The knockdown of ELOVL5 and IGFBP6 genes was also discovered to change the expression of a group of genes involved in the formation of intercellular contacts. In particular, the expression of the CDH11 gene was markedly reduced, which also complies with the correlation analysis. The spheroid formation assay showed that intercellular adhesion decreased as a result of the knockdown of the ELOVL5 and IGFBP6 genes. Thus, the obtained data indicate that malignant breast tumors with reduced expression of the ELOVL5 and IGFBP6 genes can metastasize with a higher probability due to a more efficient invasion of tumor cells.

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Algorithmic Annotation of Functional Roles for Components of 3,044 Human Molecular Pathways

Cited by 31 publications

References 55 publications

RNA-seq profiling reveals PBMC RNA as a potential biomarker for hepatocellular carcinoma

RNA-seq profiling reveals PBMC RNA as a potential biomarker for hepatocellular carcinoma

Large-Scale Transcriptomics-Driven Approach Revealed Overexpression of CRNDE as a Poor Survival Prognosis Biomarker in Glioblastoma

Effect of the Expression of ELOVL5 and IGFBP6 Genes on the Metastatic Potential of Breast Cancer Cells

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