Dataset Information

Regulatory networks in mechanotransduction reveal key genes in promoting cancer cell stemness and proliferation.

ABSTRACT: Tumor-repopulating cells (TRCs) are cancer stem cell (CSC)-like cells with highly tumorigenic and self-renewing abilities, which were selected from tumor cells in soft three-dimensional (3D) fibrin gels with unidentified mechanisms. Here we evaluated the transcriptome alteration during TRCs generation in 3D culture and revealed that a variety of molecules related with integrin/membrane and stemness were continuously altered by mechanical environment. Some key regulators such as MYC/STAT3/hsa-miR-199a-5p, were changed in the TRCs generation. They regulated membrane genes and the downstream mechanotransduction pathways such as Hippo/WNT/TGF-?/PI3K-AKT pathways, thus further affecting the expression of downstream cancer-related genes. By integrating networks for membrane proteins, the WNT pathway and cancer-related genes, we identified key molecules in the selection of TRCs, such as ATF4, SLC3A2, CCT3, and hsa-miR-199a-5p. Silencing ATF4 or CCT3 inhibited the selection and growth of TRCs whereas reduction of SLC3A2 or hsa-miR-199a-5p promoted TRCs growth. Further studies showed that CCT3 promoted cell proliferation and stemness in vitro, while its suppression inhibited TRCs-induced tumor formation. We also contemplated CCT3 as a stemness-related gene. Our findings provide insights in the mechanism of TRCs selection through transcriptome analysis.

SUBMITTER: Huang W

PROVIDER: S-EPMC6988105 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Regulatory networks in mechanotransduction reveal key genes in promoting cancer cell stemness and proliferation.

Huang Wei W Hu Hui H Zhang Qiong Q Wu Xian X Wei Fuxiang F Yang Fang F Gan Lu L Wang Ning N Yang Xiangliang X Guo An-Yuan AY

Oncogene 20190812 42

Tumor-repopulating cells (TRCs) are cancer stem cell (CSC)-like cells with highly tumorigenic and self-renewing abilities, which were selected from tumor cells in soft three-dimensional (3D) fibrin gels with unidentified mechanisms. Here we evaluated the transcriptome alteration during TRCs generation in 3D culture and revealed that a variety of molecules related with integrin/membrane and stemness were continuously altered by mechanical environment. Some key regulators such as MYC/STAT3/hsa-miR ...[more]

PMID: 31406247

Similar Datasets

Project description:PURPOSE:Prostate cancer (PCa) causes a common male urinary system malignant tumour, and the molecular mechanisms of PCa are related to the abnormal regulation of various signalling pathways. An increasing number of studies have suggested that mRNAs, miRNAs, lncRNAs, and TFs could play important roles in various biological processes that are associated with cancer pathogenesis. This study aims to reveal functional genes and investigate the underlying molecular mechanisms of PCa with bioinformatics. METHODS:Original gene expression profiles were obtained from the GSE64318 and GSE46602 datasets in the Gene Expression Omnibus (GEO). We conducted differential screens of the expression of genes (DEGs) between two groups using the online tool GEO2R based on the R software limma package. Interactions between differentially expressed miRNAs, mRNAs and lncRNAs were predicted and merged with the target genes. Co-expression of miRNAs, lncRNAs and mRNAs was selected to construct mRNA-miRNA-lncRNA interaction networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for the DEGs. Protein-protein interaction (PPI) networks were constructed, and transcription factors were annotated. Expression of hub genes in the TCGA datasets was verified to improve the reliability of our analysis. RESULTS:The results demonstrate that 60 miRNAs, 1578 mRNAs and 61 lncRNAs were differentially expressed in PCa. The mRNA-miRNA-lncRNA networks were composed of 5 miRNA nodes, 13 lncRNA nodes, and 45 mRNA nodes. The DEGs were mainly enriched in the nuclei and cytoplasm and were involved in the regulation of transcription, related to sequence-specific DNA binding, and participated in the regulation of the PI3K-Akt signalling pathway. These pathways are related to cancer and focal adhesion signalling pathways. Furthermore, we found that 5 miRNAs, 6 lncRNAs, 6 mRNAs and 2 TFs play important regulatory roles in the interaction network. The expression levels of EGFR, VEGFA, PIK3R1, DLG4, TGFBR1 and KIT were significantly different between PCa and normal prostate tissue. CONCLUSION:Based on the current study, large-scale effects of interrelated mRNAs, miRNAs, lncRNAs, and TFs established a new prostate cancer network. In addition, we conducted functional module analysis within the network. In conclusion, this study provides new insight for exploration of the molecular mechanisms of PCa and valuable clues for further research into the process of tumourigenesis and its development in PCa.

Project description:The Actinidia (kiwifruit) is an emerging fruit plant that is severely affected by salt stress in northern China. Plants have evolved several signaling network mechanisms to cope with the detrimental effects of salt stress. To date, no reported work is available on metabolic and molecular mechanisms involved in kiwifruit salt tolerance. Therefore, the present study aims to decipher intricate adaptive responses of two contrasting salt tolerance kiwifruit species Actinidia valvata [ZMH (an important genotype), hereafter referred to as R] and Actinidia deliciosa ['Hayward' (an important green-fleshed cultivar), hereafter referred to as H] under 0.4% (w/w) salt stress for time courses of 0, 12, 24, and 72 hours (hereafter refered to as h) by combined transcriptome and metabolome analysis. Data revealed that kiwifruit displayed specific enrichment of differentially expressed genes (DEGs) under salt stress. Interestingly, roots of R plants showed a differential expression pattern for up-regulated genes. The KEGG pathway analysis revealed the enrichment of DEGs related to plant hormone signal transduction, glycine metabolism, serine and threonine metabolism, glutathione metabolism, and pyruvate metabolism in the roots of R under salt stress. The WGCNA resulted in the identification of five candidate genes related to glycine betaine (GB), pyruvate, total soluble sugars (TSS), and glutathione biosynthesis in kiwifruit. An integrated study of transcriptome and metabolome identified several genes encoding metabolites involved in pyruvate metabolism. Furthermore, several genes encoding transcription factors were mainly induced in R under salt stress. Functional validation results for overexpression of a candidate gene betaine aldehyde dehydrogenase (AvBADH, R_transcript_80484) from R showed significantly improved salt tolerance in Arabidopsis thaliana (hereafter referred to as At) and Actinidia chinensis ['Hongyang' (an important red-fleshed cultivar), hereafter referred to as Ac] transgenic plants than in WT plants. All in all, salt stress tolerance in kiwifruit roots is an intricate regulatory mechanism that consists of several genes encoding specific metabolites.

Project description:BackgroundWith the gradual unveiling of tumour heterogeneity, cancer stem cells (CSCs) are now being considered the initial component of tumour initiation. However, the mechanisms of the growth and maintenance of breast cancer (BRCA) stem cells are still unknown.MethodsTo explore the crucial genes modulating BRCA stemness characteristics, we combined the gene expression value and mRNA expression-based stemness index (mRNAsi) of samples from The Cancer Genome Atlas (TCGA), and the mRNAsi was corrected using the tumour purity (corrected mRNAsi). mRNAsi and corrected mRNAsi were analysed and showed a close relationship with BRCA clinical characteristics, including tumour depth, pathological staging and survival status. Next, weighted gene co-expression network analysis (WGCNA) was applied to distinguish crucial gene modules and key genes. A series of functional analyses and expression validation of key genes were conducted using multiple databases, including Oncomine, Gene Expression Omnibus (GEO) and Gene Expression Profiling Integrative Analysis (GEPIA).ResultsThis study found that mRNAsi and corrected mRNAsi scores were higher in BRCA tissues than that in normal tissues, and both of them increased with tumour stage. Higher corrected mRNAsi scores showed worse overall survival outcomes. We screened 3 modules and 32 key genes, and those key genes were found to be strongly correlated with each other. Functional analysis revealed that the key genes were related to cell fate decision events such as the cell cycle, cellular senescence, chromosome segregation and mitotic nuclear division. Among 32 key genes, we identified 12 genes that strongly correlated with BRCA survival.ConclusionsThirty-two genes were found to be closely related to BRCA stem cell characteristics; among them, 12 genes showed prognosis-oriented effects in BRCA patients. The most significant signalling pathway related to stemness in BRCA was the cell cycle pathway, which may support new ideas for screening therapeutic targets to inhibit BRCA stem characteristics. These findings may highlight some therapeutic targets for inhibiting BRCA stem cells.

Dataset Information

Regulatory networks in mechanotransduction reveal key genes in promoting cancer cell stemness and proliferation.

Publications

Regulatory networks in mechanotransduction reveal key genes in promoting cancer cell stemness and proliferation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets