Breast cancer treatment can be improved with biomarkers for early detection and individualized therapy. A set of 86 microRNAs (miRNAs) were identified to separate breast cancer tumors from normal breast tissues (n = 52) with an overall accuracy of 90.4%. Six miRNAs had concordant expression in both tumors and breast cancer patient blood samples compared with the normal control samples. Twelve miRNAs showed concordant expression in tumors vs. normal breast tissues and patient survival (n = 1093), with seven as potential tumor suppressors and five as potential oncomiRs. From experimentally validated target genes of these 86 miRNAs, pan-sensitive and pan-resistant genes with concordant mRNA and protein expression associated with in-vitro drug response to 19 NCCN-recommended breast cancer drugs were selected. Combined with in-vitro proliferation assays using CRISPR-Cas9/RNAi and patient survival analysis, MEK inhibitors PD19830 and BRD-K12244279, pilocarpine, and tremorine were discovered as potential new drug options for treating breast cancer. Multi-omics biomarkers of response to the discovered drugs were identified using human breast cancer cell lines. This study presented an artificial intelligence pipeline of miRNA-based discovery of biomarkers, therapeutic targets, and repositioning drugs that can be applied to many cancer types.
The majority of lung cancer patients are diagnosed with metastatic disease. This study identified a set of 73 microRNAs (miRNAs) that classified lung cancer tumors from normal lung tissues with an overall accuracy of 96.3% in the training patient cohort (n = 109) and 91.7% in unsupervised classification and 92.3% in supervised classification in the validation set (n = 375). Based on association with patient survival (n = 1016), 10 miRNAs were identified as potential tumor suppressors (hsa-miR-144, hsa-miR-195, hsa-miR-223, hsa-miR-30a, hsa-miR-30b, hsa-miR-30d, hsa-miR-335, hsa-miR-363, hsa-miR-451, and hsa-miR-99a), and 4 were identified as potential oncogenes (hsa-miR-21, hsa-miR-31, hsa-miR-411, and hsa-miR-494) in lung cancer. Experimentally confirmed target genes were identified for the 73 diagnostic miRNAs, from which proliferation genes were selected from CRISPR-Cas9/RNA interference (RNAi) screening assays. Pansensitive and panresistant genes to 21 NCCN-recommended drugs with concordant mRNA and protein expression were identified. DGKE and WDR47 were found with significant associations with responses to both systemic therapies and radiotherapy in lung cancer. Based on our identified miRNA-regulated molecular machinery, an inhibitor of PDK1/Akt BX-912, an anthracycline antibiotic daunorubicin, and a multi-targeted protein kinase inhibitor midostaurin were discovered as potential repositioning drugs for treating lung cancer. These findings have implications for improving lung cancer diagnosis, optimizing treatment selection, and discovering new drug options for better patient outcomes.
more » « less- NSF-PAR ID:
- 10466597
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- Cancers
- Volume:
- 15
- Issue:
- 8
- ISSN:
- 2072-6694
- Page Range / eLocation ID:
- 2294
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Recent genome-wide studies have begun to identify gene variants, expression profiles, and regulators associated with neuroticism, anxiety disorders, and depression. We conducted a set of experimental cell culture studies of gene regulation by micro RNAs (miRNAs), based on genome-wide transcriptome, proteome, and miRNA expression data from twenty
postmortem samples of lateral amygdala from donors with known neuroticism scores. Using Ingenuity Pathway Analysis and TargetScan, we identified a list of mRNA–protein–miRNA sets whose expression patterns were consistent with miRNA-based translational repression, as a function of trait anxiety. Here, we focused on one gene from that list, which is of particular translational significance in Psychiatry: synaptic vesicle glycoprotein 2A (SV2A) is the binding site of the anticonvulsant drug levetiracetam ((S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide), which has shown promise in anxiety disorder treatments. We confirmed thatSV2A is associated with neuroticism or anxiety using an original GWAS of a community cohort (N = 1,706), and cross-referencing a published GWAS of multiple cohorts (Ns ranging from 340,569 to 390,278).Postmortem amygdala expression profiling implicated three putative regulatory miRNAs to targetSV2A : miR-133a, miR-138, and miR-218. Moving from association to experimental causal testing in cell culture, we used a luciferase assay to demonstrate that miR-133a and miR-218, but not miR-138, significantly decreased relative luciferase activity from theSV2A dual-luciferase construct. In human neuroblastoma cells, transfection with miR-133a and miR-218 reduced both endogenousSV2A mRNA and protein levels, confirming miRNA targeting of theSV2A gene. This study illustrates the utility of combiningpostmortem gene expression data with GWAS to guide experimental cell culture assays examining gene regulatory mechanisms that may contribute to complex human traits. Identifying specific molecular mechanisms of gene regulation may be useful for future clinical applications in anxiety disorders or other forms of psychopathology. -
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Abstract Background Many studies have investigated microRNAs (miRNAs) in the detection of type 2 diabetes mellitus (T2DM). Herein, the dysregulated direction of stress‐related miRNAs used as biomarkers of T2DM are summarized and analyzed.
Methods PubMed, EMBASE, ISI Web of Science, and three Chinese databases were searched for case–control miRNA profiling studies about T2DM. A meta‐analysis under a random effect was performed. Subgroup analysis was conducted based on different tissues and species. Sensitivity analysis was conducted to confirm the robustness among studies. The effect size was pooled using ln odds ratios (ORs), 95% confidence intervals (95% CIs), and
P‐ values.Results The present meta‐analysis included 39 case–control studies with a total of 494 miRNAs. Only 33 miRNAs were reported in three or more studies and, of these, 18 were inconsistent in their direction of dysregulation. Two significantly dysregulated miRNAs (let‐7 g and miR‐155) were identified in the meta‐analysis. Four miRNAs (miR‐142‐3p, miR‐155, miR‐21, and miR‐34c‐5p) were dysregulated in patients with T2DM, whereas five miRNAs (miR‐146a, miR‐199a‐3p, miR‐200b, miR‐29b and miR‐30e) were dysregulated in animal models of diabetes. In addition, two dysregulated miRNAs (miR‐146a and miR‐21) were highly cornea specific and heart specific. In sensitivity analysis, only miR‐155 was still significantly dysregulated after removing studies with small sample sizes.
Conclusions The present meta‐analysis revealed that 16 stress‐related miRNAs were significantly dysregulated in T2DM. MiR‐148b, miR‐223, miR‐130a, miR‐19a, miR‐26b and miR‐27b were selected as potential circulating biomarkers of T2DM. In addition, miR‐146a and miR‐21 were identified as potential tissue biomarkers of T2DM.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/cancers15082294
