Inverse Impact of Cancer Drugs on Circular and Linear RNAs in Breast Cancer Cell Lines.

Altered expression of circular RNAs (circRNAs) has previously been investigated in breast cancer. However, little is known about the effects of drugs on their regulation and relationship with the cognate linear transcript (linRNA). We analyzed the dysregulation of both 12 cancer-related circRNAs and their linRNAs in two breast cancer cell lines undergoing various treatments. We selected 14 well-known anticancer agents affecting different cellular pathways and examined their impact. Upon drug exposure circRNA/linRNA expression ratios increased, as a result of the downregulation of linRNA and upregulation of circRNA within the same gene. In this study, we highlighted the relevance of identifying the drug-regulated circ/linRNAs according to their oncogenic or anticancer role. Interestingly, VRK1 and MAN1A2 were increased by several drugs in both cell lines. However, they display opposite effects, circ/linVRK1 favors apoptosis whereas circ/linMAN1A2 stimulates cell migration, and only XL765 did not alter the ratio of other dangerous circ/linRNAs in MCF-7. In MDA-MB-231 cells, AMG511 and GSK1070916 decreased circGFRA1, as a good response to drugs. Furthermore, some circRNAs might be associated with specific mutated pathways, such as the PI3K/AKT in MCF-7 cells with circ/linHIPK3 correlating to cancer progression and drug-resistance, or NHEJ DNA repair pathway in TP-53 mutated MDA-MB-231 cells.

Circular RNAs Could Encode Unique Proteins and Affect Cancer Pathways.

circRNAs constitute a novel class of RNA, generally considered as non-coding RNAs; nonetheless, their coding potential has been under scrutiny. In this work, we systematically explored the predicted proteins of more than 160,000 circRNAs detected by exome capture RNA-sequencing and collected in the MiOncoCirc pan-cancer compendium, including normal and cancer samples from different types of tissues. For the functional evaluation, we compared their primary structure and domain composition with those derived from the same linear mRNAs. Among the 4362 circRNAs potentially encoding proteins with a unique primary structure and 1179 encoding proteins with a novel domain composition, 183 were differentially expressed in cancer. In particular, eight were associated with prognosis in acute myeloid leukemia. The functional classification of the dysregulated circRNA-encoded polypeptides showed an enrichment in the heme and cancer signaling, DNA-binding, and phosphorylation processes, and disclosed the roles of some circRNA-based effectors in cancer.

The role of non-coding RNAs in neuroinflammatory process in multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system chronic neuroinflammatory disease followed by neurodegeneration. The diagnosis is based on clinical presentation, cerebrospinal fluid testing and magnetic resonance imagining. There is still a lack of a diagnostic blood-based biomarker for MS. Due to the cost and difficulty of diagnosis, new and more easily accessible methods are being sought. New biomarkers should also allow for early diagnosis. Additionally, the treatment of MS should lead to the personalization of the therapy. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as well as their target genes participate in pathophysiology processes in MS. Although the detailed mechanism of action of non-coding RNAs (ncRNAs, including miRNAs and lncRNAs) on neuroinflammation in MS has not been fully explained, several studies were conducted aiming to analyse their impact in MS. In this article, we review up-to-date knowledge on the latest research concerning the ncRNAs in MS and evaluate their role in neuroinflammation. We also point out the most promising ncRNAs which may be promising in MS as diagnostic and prognostic biomarkers.

Altered Circulating MicroRNA Profiles After Endurance Training: A Cohort Study of Ultramarathon Runners.

BACKGROUND: Despite the positive effects of endurance training on the cardiovascular (CV) system, excessive exercise induces not only physiological adaptations but also adverse changes in CV system, including the heart. We aimed to evaluate the selected miRNAs expression based on bioinformatic analysis and their changes before and after an ultramarathon run. MATERIALS AND METHODS: Cardiac tissue-specific targets were identified with the Tissue 2.0 database. Gene-gene interaction data were retrieved from the STRING app for Cytoscape. Twenty-three endurance athletes were recruited to the study. Athletes ran to completion (100 km) or exhaustion (52-91 km, median 74 km). All participants completed pre- and post-run testing. miRNAs expressions were measured both before and after the race. RESULTS: Enrichment analysis of the signaling pathways associated with the genes targeted by miRNAs selected for qRT-PCR validation (miR-1-3p, miR-126, miR-223, miR-125a-5p, miR-106a-5p, and miR-15a/b). All selected miRNAs showed overlap in regulation in pathways associated with cancer, IL-2 signaling, TGF-ß signaling as well as BDNF signaling pathway. Analysis of metabolites revealed significant regulation of magnesium and guanosine triphosphate across analyzed miRNA targets. MiR-1-3p, miR-125a-5p, miR-126, and miR-223 expressions were measured in 23 experienced endurance athletes, before and after an ultramarathon wherein athletes ran to completion (100 km) or exhaustion (52-91 km, median 74 km). The expressions of miR-125a-5p, miR-126, and miR-223 were significantly increased after the race (p = 0.007, p = 0.001, p = 0.014, respectively). MiR-1-3p expression post-run showed a negative correlation with the post-run levels of high-sensitivity C-reactive protein (hs-CRP) (r = -0.632, p = 0.003). Higher miR-1-3p expression was found in runners, who finished the race under 10 h compared to runners who finished over 10 h (p = 0.001). Post-run miR-125a-5p expression showed a negative correlation with the peak lactate during the run (r = -0.576, p = 0.019). CONCLUSION: Extreme physical activity, as exemplified by an ultramarathon, is associated with changes in circulating miRNAs' expression related to inflammation, fibrosis, and cardiac muscle function. In particular, the negative correlations between miR-125a-5p and lactate concentrations, and miR-1-3p and hs-CRP, support their role in specific exercise-induced adaptation. Further studies are essential to validate the long-term effect of these observations.

Theoretical and experimental comparisons of gene expression indexes for oligonucleotide arrays.

MOTIVATION: Oligonucleotide expression arrays exhibit systematic and reproducible variation produced by the multiple distinct probes used to represent a gene. Recently, a gene expression index has been proposed that explicitly models probe effects, and provides improved fits of hybridization intensity for arrays containing perfect match (PM) and mismatch (MM) probe pairs. RESULTS: Here we use a combination of analytical arguments and empirical data to show directly that the estimates provided by model-based expression indexes are superior to those provided by commercial software. The improvement is greatest for genes in which probe effects vary substantially, and modeling the PM and MM intensities separately is superior to using the PM-MM differences. To empirically compare expression indexes, we designed a mixing experiment involving three groups of human fibroblast cells (serum starved, serum stimulated, and a 50:50 mixture of starved/stimulated), with six replicate HuGeneFL arrays in each group. Careful spiking of control genes provides evidence that 88-98% of the genes on the array are detectably transcribed, and that the model-based estimates can accurately detect the presence versus absence of a gene. The use of extensive replication from single RNA sources enables exploration of the technical variability of the array.