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Plasma MicroRNA-16 Is a Biomarker for Diagnosis, Stratification, and Prognosis of Hyperacute Cerebral Infarction

ABSTRACT: Indices for diagnosis of hyperacute cerebral infarction (HACI) and prediction of prognosis are essential for timely and appropriate management. MicroRNAs(miRNAs) regulating gene expression following stroke have potential use as prognostic markers of HACI. Here, we explored whether concentrations of circulating miRNAs could be correlated with clinical outcomes and thus form the basis of a system of stroke stratification. Plasma samples from patients with HACI (n = 7) and age-matched healthy volunteers (HVT, n = 4) were screened by microarray to find differentially expressed miRNAs, which were further verified by quantitative reverse transcription polymerase chain reaction(qRT-PCR) (HACI:HVT = 33:23). The target genes of the miRNAs with verified differential expression were investigated by GO and KEEG analysis. Using the TOAST (OCSP) criteria and the 3-month modified Rankin Score(mRS), relationships between the expression patterns of specific miRNAs, stroke stratification，and clinical prognosis were determined. The microarray analysis revealed 12 differentially expressed miRNAs. Among seven selected miRNAs verified with qRT-PCR, miR-16 expression in the HACI group was the most significantly different from the HVT group (P < 0.01). Bioinformatics analysis showed that the potential target genes of miR-16 were mainly involved in programmed cell death and the p53 signaling pathways. Receiver operating characteristic(ROC) analysis showed that the area under curve(AUC) of miR-16 was 0.775 (sensitivity 69.7% and specificity 87%) and 0.952 (sensitivity 100% and specificity 91.3%) in overall patients and patients with large artery atherosclerosis (LAAS), respectively. Elevated miR-16 expression was associated with the stroke subtype of LAAS, total anterior circulation infarction, partial anterior circulation infarction, and poor prognosis (P < 0.05). A diagnostic method based on rapid measurement of plasma miR-16 has potential to identify hyperacute cerebral infarction with LAAS with high sensitivity and specificity, which would inform and improve early treatment decisions and disease management.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86291 | GEO | 2016/09/01

SECONDARY ACCESSION(S): PRJNA341365

REPOSITORIES: GEO

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Project description:Rationale: Currently, there are no blood-based biomarkers with clinical utility for acute ischemic stroke (IS). microRNAs (miRNAs) show promise as disease markers due to their cell-type specific expression patterns and stability in peripheral blood. Objective: To identify circulating miRNAs associated with acute IS, determine their temporal course up to 90 days post-stroke, and explore their utility as an early diagnostic marker. Methods and Results: We used RNA sequencing to study expression changes of circulating miRNAs in a discovery sample of 20 IS patients and 20 matched healthy control subjects (HCs). We further applied qRT-PCR in independent samples for validation (40 IS patients and 40 matched controls), replication (200 IS patients, 100 HCs), and in 72 patients with transient ischemic attacks (TIA). Sampling of patient plasma was done immediately upon hospital arrival. We identified, validated, and replicated three differentially expressed miRNAs, which were upregulated in IS patients compared to both HCs (miR-125a-5p [1.8-fold; P=1.5x10-6], miR-125b-5p [2.5-fold; P=5.6x10-6], and miR-143-3p [4.8-fold; P=7.8x10-9]) and TIA patients (miR-125a-5p: P=0.003, miR-125b-5p: P=0.003, miR-143-3p: P=0.005). Longitudinal analysis of expression levels up to 90 days after stroke revealed a normalization to control levels for miR-125b-5p and miR-143-3p starting at day two, while miR-125a-5p remained elevated. Levels of all three miRNAs depended on platelet numbers in a platelet spike-in experiment, but were unaffected by chemical hypoxia in N2a cells and in experimental stroke models. In a random forest classification, miR-125a-5p, miR-125b-5p and miR-143-3p differentiated between HCs and IS patients with an area under the curve (AUC) of 0.90 (sensitivity: 85.6%; specificity: 76.3%), which was superior to multimodal cranial computed tomography obtained for routine diagnostics (sensitivity: 72.5%) and previously reported biomarkers of acute IS (neuron specific enolase: AUC=0.69, interleukin 6: AUC=0.82). Conclusions: A set of circulating miRNAs (miR-125a-5p, miR-125b-5p, miR-143-3p) associates with acute IS and might have clinical utility as an early diagnostic marker.

Project description:Introduction: MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in post-transcriptional gene regulation and have recently been shown to play a role in cancer metastasis. In solid tumors, especially breast cancer, alterations in miRNA expression contribute to cancer pathogenesis, including metastasis. Considering the emerging role of miRNAs in metastasis, the identification of predictive markers is necessary to further understanding of stage-specific breast cancer development. This is a retrospective analysis that aimed to identify molecular biomarkers related to distant breast cancer metastasis development. Methods: A retrospective case cohort study was performed in 64 breast cancer patients treated during the period from 1998-2001. The case group (n=29) consisted of patients with a poor prognosis who presented with breast cancer recurrence or metastasis during follow up. The control group (n=35) consisted of a random sample of patients with a good prognosis who did not develop breast cancer recurrence or metastasis. These patient groups were stratified according to TNM clinical stage (CS) I, II and III, and the main clinical features of the patients were homogeneous. miRNA profiling was performed using formalin-fixed, paraffin-embedded tumors. Biomarkers related to metastatic potential were identified independent of clinical stage, and a cutoff point was selected based on the optimal sensitivity and specificity (ROC curve). Finally, a hazard risk analysis of these biomarkers was performed to evaluate their relation to metastatic potential. Results: miRNA expression profiling identified several miRNAs that were either specific and shared across all clinical stages (p?0.05). Among these, we identified miRNAs previously associated with cell motility (let-7 family), cell proliferation and invasion (hsa-miR-16 and has-miR-205) and distant metastasis (hsa-miR-21). In addition, hsa-miR-494 and hsa-miR-21 were up-regulated in metastatic cases of CSI and II. Furthermore, the combination of the 3 miRNAs identified for CSII (hsa-miR-494, hsa-miR-183 and hsa-miR-21) was significant and were a more effective risk marker compared to the single miRNAs. Conclusions: Women with metastatic breast cancer, especially CSII, presented up-regulated levels of miR-183, miR-494 and miR-21, which were associated with a poor prognosis. These miRNAs therefore represent new risk biomarkers of breast cancer metastasis and may be useful for future targeted therapies.

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Plasma MicroRNA-16 Is a Biomarker for Diagnosis, Stratification, and Prognosis of Hyperacute Cerebral Infarction

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