Dataset Information

MiRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment.

ABSTRACT: microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer's disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications.

SUBMITTER: Conti I

PROVIDER: S-EPMC7016744 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment.

Conti Ilaria I Varano Gabriele G Simioni Carolina C Laface Ilaria I Milani Daniela D Rimondi Erika E Neri Luca M LM

Cells 20200115 1

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, i ...[more]

PMID: 31952362

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Project description:Background: Immunosuppressive cell interactions are responsible for tumor progression and metastasis, as well as anti-tumor immune dysfunction. However, the communication pattern remains unclear. Methods: We first integrated two single-cell RNA-seq datasets (GSE72056 and GSE103322) of different tumor types to increase the diversity of immunosuppressive cells. Then, based on the analysis results of the communication network, gene regulatory network (GRN), and highly activated pathways, we identified the hub gene in the immunosuppressive tumor microenvironment (TME). To further explore the molecular features of the identified gene, we performed several in silico analysis and in vitro experiments including qRT-PCR and CCK-8 assay. Results: Four types of immunosuppressive cells were identified, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and regulatory T cells (Tregs). Based on GRNs and the interactions of immunosuppressive cells and tumor cells, we constructed an intercellular communication signature that divided the pan-cancer TME into two clusters with distinct immunological features and different responses to immunotherapy. In combination with pathway analysis, JunB proto-oncogene (JUNB) was identified as the hub gene of the immunosuppressive TME, and it designed a non-inflamed TME of bladder cancer according to evidence that JUNB was negatively correlated with immunomodulators, chemokines, major histocompatibility complex molecules, immune cell infiltration abundances, anti-cancer immune response, and immune checkpoint inhibitors. Moreover, JUNB may predict an unfavorable response to immunotherapy. The signaling network of the four types of cells demonstrated the dominant roles of CAFs and TAMs in the TME. Further investigation uncovered that the complement signal was highly activated in the interactions between subpopulations of the inflammatory phenotype of CAFs and TAMs. Functional experiment results demonstrated the upregulated JUNB in bladder cancer tissues and low-immunity-score tissues. In addition, CAFs showed a pro-tumor proliferation effect via JUNB. Conclusion: Our findings gave insights into the immunosuppressive TME communication network and provided potential therapeutic targets.

Project description:BackgroundDisulfidptosis, an emerging type of programmed cell death, plays a pivotal role in various cancer types, notably impacting the progression of kidney renal clear cell carcinoma (KIRC) through the tumor microenvironment (TME). However, the specific involvement of disulfidptosis within the TME remains elusive.MethodsAnalyzing 41,784 single cells obtained from seven samples of KIRC through single-cell RNA sequencing (scRNA-seq), this study employed nonnegative matrix factorization (NMF) to assess 24 disulfidptosis regulators. Pseudotime analysis, intercellular communication mapping, determination of transcription factor activities (TFs), and metabolic profiling of the TME subgroup in KIRC were conducted using Monocle, CellChat, SCENIC, and scMetabolism. Additionally, public cohorts were utilized to predict prognosis and immune responses within the TME subgroup of KIRC.ResultsThrough NMF clustering and differential expression marker genes, fibroblasts, macrophages, monocytes, T cells, and B cells were categorized into four to six distinct subgroups. Furthermore, this investigation revealed the correlation between disulfidptosis regulatory factors and the biological traits, as well as the pseudotime trajectories of TME subgroups. Notably, disulfidptosis-mediated TME subgroups (DSTN+CD4T-C1 and FLNA+CD4T-C2) demonstrated significant prognostic value and immune responses in patients with KIRC. Multiple immunohistochemistry (mIHC) assays identified marker expression within both cell clusters. Moreover, CellChat analysis unveiled diverse and extensive interactions between disulfidptosis-mediated TME subgroups and tumor epithelial cells, highlighting the TNFSF12-TNFRSF12A ligand-receptor pair as mediators between DSTN+CD4T-C1, FLNA+CD4T-C2, and epithelial cells.ConclusionOur study sheds light on the role of disulfidptosis-mediated intercellular communication in regulating the biological characteristics of the TME. These findings offer valuable insights for patients with KIRC, potentially guiding personalized immunotherapy approaches.

Dataset Information

MiRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment.

Publications

miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment.

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