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Regulation rewiring analysis reveals mutual regulation between STAT1 and miR-155-5p in tumor immunosurveillance in seven major cancers.

ABSTRACT: Transcription factors (TFs) and microRNAs (miRNAs) form a gene regulatory network (GRN) at the transcriptional and post-transcriptional level in living cells. However, this network has not been well characterized, especially in regards to the mutual regulations between TFs and miRNAs in cancers. In this study, we collected those regulations inferred by ChIP-Seq or CLIP-Seq to construct the GRN formed by TFs, miRNAs, and target genes. To increase the reliability of the proposed network and examine the regulation activity of TFs and miRNAs, we further incorporated the mRNA and miRNA expression profiles in seven cancer types using The Cancer Genome Atlas data. We observed that regulation rewiring was prevalent during tumorigenesis and found that the rewired regulatory feedback loops formed by TFs and miRNAs were highly associated with cancer. Interestingly, we identified one regulatory feedback loop between STAT1 and miR-155-5p that is consistently activated in all seven cancer types with its function to regulate tumor-related biological processes. Our results provide insights on the losing equilibrium of the regulatory feedback loop between STAT1 and miR-155-5p influencing tumorigenesis.

SUBMITTER: Lin CC

PROVIDER: S-EPMC4496795 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Regulation rewiring analysis reveals mutual regulation between STAT1 and miR-155-5p in tumor immunosurveillance in seven major cancers.

Lin Chen-Ching CC Jiang Wei W Mitra Ramkrishna R Cheng Feixiong F Yu Hui H Zhao Zhongming Z

Scientific reports 20150709

Transcription factors (TFs) and microRNAs (miRNAs) form a gene regulatory network (GRN) at the transcriptional and post-transcriptional level in living cells. However, this network has not been well characterized, especially in regards to the mutual regulations between TFs and miRNAs in cancers. In this study, we collected those regulations inferred by ChIP-Seq or CLIP-Seq to construct the GRN formed by TFs, miRNAs, and target genes. To increase the reliability of the proposed network and examin ...[more]

PMID: 26156524

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Project description:Introduction: Acute graft vs. host disease (aGvHD) is a frequent complication following allogeneic haematopoeitic transplantation (HSCT). Despite recent advances, there are no universally accepted biomarkers to determine development of aGvHD. MicroRNAs miR-146a and miR-155 have been previously associated with aGvHD and show promise as clinically translatable biomarkers. In this study, we performed comprehensive expression profiling of miR-146a, miR-155, and miR-155* expression in aGvHD target tissue and biofluids and relate expression to post-HSCT outcomes. Materials and Methods: MicroRNA expression was assessed by qRT-PCR in gastrointestinal (n = 31) and skin (n = 31) biopsies as well as serum (exploratory cohort n = 34, verification cohort n = 81, diagnostic cohort n = 65) and urine (exploratory cohort n = 30, verification cohort n = 56, diagnostic cohort n = 20) biofluids, including extracellular vesicle (EV) cohorts (serum EV n = 15, urine EV n = 30). Expression was related to aGvHD incidence, severity and overall survival. Results: In GI samples, expression of miR-155 (p = 0.03) and miR-146a (p = 0.03) was higher at aGvHD onset compared to patients with no GvHD. In skin biopsies, expression of miR-155 (p = 0.004) was upregulated in aGvHD patients compared to normal control skin. Expression of miR-146a was higher in aGvHD compared to no aGvHD biopsies (p = 0.002). In serum, miR-155 (p = 0.03) and miR-146a (p = 0.02) expression was higher at day 14 (D14), while in urine expression was elevated at D7 post-HSCT in patients who developed aGvHD compared to those disease-free. This was verified in an independent serum (miR-155 p = 0.005, miR-146a p = 0.003) and urine (miR-155 p = 0.02, miR-146a p = 0.04) cohort, where both microRNAs were also associated with aGvHD by ROC analysis. In serum and urine samples taken at the time of aGvHD symptoms, expression of miR-155 and miR-146a was also elevated (serum miR-155 p = 0.03, miR-146a p < 0.001; urine miR-155 p = 0.02, miR-146a p = 0.02). In contrast, miR-146a and miR-155 were downregulated at D14 in serum EVs and at D7 in urine EVs in patients who developed aGvHD compared to those that remained disease-free, in both an exploratory (serum miR-155 p = 0.02, miR-146a p = 0.06; urine miR-155 p = 0.02, miR-146a p = 0.07) and an independent cohort (serum miR-155 p = 0.01, miR-146a p = 0.02). Conclusions: These results further support a role for miR-155 and miR-146a as non-invasive, clinically relevant biomarkers for aGvHD. However, the link between their involvement in generalized inflammation and in specific pathophysiology requires further investigation at a systemic level.

Project description:BackgroundNon-small cell lung cancer (NSCLC) ranks first for mortality among all malignancies. Squamous cell carcinoma (SCC) is one of the main types of NSCLC. Previous studies have found that fibroblast growth factor 9 (FGF9) is closely related to lung SCC via different molecular regulatory mechanisms. This study aimed to explore the relationship between microRNA-155-5p (miR-155-5p) and FGF9 gene expression and their effects on the proliferation and invasion of lung SCC through experiments, in order to provide theoretical basis for overcoming this disease.MethodsFluorescence quantitative polymerase chain reaction was employed for the detection miR-155-5p and FGF9 expression in lung SCC tissues (n=40) and the corresponding adjacent normal tissues. The expression of FGF9 in the cancerous and adjacent tissues was detected by western blot. Transwell assay used to verify the effect of miR-155-5p on FGF-induced invasion and migration. Finally, subcutaneous tumor formation experiments in nude mice were used to verify how miR-155-5p and FGF9 affect the proliferative ability of lung SCC cells.ResultsThe results of fluorescence quantitative PCR revealed that miR-155-5p and FGF9 were expressed at high and low levels, respectively, in lung SCC tissue samples relative to normal adjacent tissue samples. Western blot analysis of 6 lung SCC tissue samples revealed a significantly reduced level of FGF9. Correlation analysis uncovered that miR-155-5p and FGF9 share a significant negative correlation in lung SCC. At the messenger RNA and protein levels miR-155-5p could negatively regulate the expression of FGF9. Bioinformatics and dual luciferase reporter assay results confirmed FGF9 to be a downstream regulatory gene targeted by miR-155-5p. Our in vitro and in vivo results demonstrated that FGF9 overexpression exerted a significant inhibitory effect on miR-155-5p's ability to promote lung cancer cell growth, invasion, and proliferation.ConclusionsOur results show that miR-155-5p, as an oncogene, negative regulates FGF9 expression to promote SCC occurrence and development in the lungs.

Dataset Information

Regulation rewiring analysis reveals mutual regulation between STAT1 and miR-155-5p in tumor immunosurveillance in seven major cancers.

Publications

Regulation rewiring analysis reveals mutual regulation between STAT1 and miR-155-5p in tumor immunosurveillance in seven major cancers.

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