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Identification of four novel serum protein biomarkers in sepsis patients encoded by target genes of sepsis-related miRNAs.

Wang HJ, Wang BZ, Zhang PJ, Deng J, Zhao ZR, Zhang X, Xiao K, Feng D, Jia YH, Liu YN, Xie LX - Clin. Sci. (2014)

Bottom Line: DUSP3 levels were not significantly different between any groups.When the value of predictive probabilities was 0.449, the four proteins yielded a sensitivity of 68% and a specificity of 91%.Dynamic changes in ACVR2A, FOXO1 and IHH levels showed differential expression between survivors and non-survivors at all time points.

View Article: PubMed Central - PubMed

Affiliation: ‡Department of Respiratory Medicine, the Affiliated Beijing Tiantan Hospital of Capital Medical University, Beijing, 100050, China.

ABSTRACT
The goal of the present study was to identify novel protein biomarkers from the target genes of six serum miRNAs that we identified previously in patients with sepsis. The target genes were predicted by bioinformatics analysis; the levels of the respective proteins in the sera of patients with sepsis were detected by ELISA. ACVR2A (activin A receptor, type IIA), FOXO1 (forkhead box O1), IHH (Indian hedgehog), STK4 (serine/threonine kinase 4) and DUSP3 (dual specificity phosphatase 3) were predicted to be the targets of the six miRNAs, and their encoded proteins were used for biomarker identification. Levels of ACVR2A (P<0.01) and FOXO1 (P<0.01) were significantly different among normal controls, patients with sepsis, patients with severe sepsis and patients with septic shock. Furthermore, levels of ACVR2A (P=0.025), FOXO1 (P<0.001), IHH (P=0.001) and STK4 (P=0.001) were differentially expressed in survivors and non-survivors. DUSP3 levels were not significantly different between any groups. Conjoin analysis of the four differentially expressed proteins showed that the area under the curve of the predictive probabilities was 0.875 [95% CI (confidence interval): 0.785-0.965], which was higher than the SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. When the value of predictive probabilities was 0.449, the four proteins yielded a sensitivity of 68% and a specificity of 91%. Dynamic changes in ACVR2A, FOXO1 and IHH levels showed differential expression between survivors and non-survivors at all time points. On the basis of a combined analysis of the four identified proteins, their predictive value of 28-day mortality of patients with sepsis was better than the SOFA or APACHE II scores.

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The network of miRNAs (A), their target genes and the degrees for each miRNA(B)
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Figure 2: The network of miRNAs (A), their target genes and the degrees for each miRNA(B)

Mentions: To analyse the interactions between the miRNAs and genes, a miRNA–gene network was built(Figure 2A). In this network, ACVR2A (activinA receptor, type IIA), FOXO1 (forkhead box O1) and SLC4A4(solute carrier family 4, member 4) were the common target genes of miR-223,miR-15a and miR-16 (with a degree of 3). IHH(Indian hedgehog) was the common target gene of miR-122 andmiR-15a with a degree of 2. FRS2 (factor receptor substrate 2) wasthe common target gene of miR-193b* and miR-16. AlthoughSTK4 (serine/threonine kinase 4) and DUSP3 (dual specificityphosphatase 3) were only target genes of miR-193b*, these two genes werealso selected because the level of miR-193b* had the highest predictivevalue of sepsis mortality [19] (Table 1). According to the KEGG pathway database, SLC4A4 is onlyinvolved in pancreatic and bile secretion, and FRS2 is only involved in theneurotrophin signalling pathway. Therefore we selected ACVR2A,FOXO1, IHH, STK4 and DUSP3 forfurther biomarker identification.


Identification of four novel serum protein biomarkers in sepsis patients encoded by target genes of sepsis-related miRNAs.

Wang HJ, Wang BZ, Zhang PJ, Deng J, Zhao ZR, Zhang X, Xiao K, Feng D, Jia YH, Liu YN, Xie LX - Clin. Sci. (2014)

The network of miRNAs (A), their target genes and the degrees for each miRNA(B)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4202716&req=5

Figure 2: The network of miRNAs (A), their target genes and the degrees for each miRNA(B)
Mentions: To analyse the interactions between the miRNAs and genes, a miRNA–gene network was built(Figure 2A). In this network, ACVR2A (activinA receptor, type IIA), FOXO1 (forkhead box O1) and SLC4A4(solute carrier family 4, member 4) were the common target genes of miR-223,miR-15a and miR-16 (with a degree of 3). IHH(Indian hedgehog) was the common target gene of miR-122 andmiR-15a with a degree of 2. FRS2 (factor receptor substrate 2) wasthe common target gene of miR-193b* and miR-16. AlthoughSTK4 (serine/threonine kinase 4) and DUSP3 (dual specificityphosphatase 3) were only target genes of miR-193b*, these two genes werealso selected because the level of miR-193b* had the highest predictivevalue of sepsis mortality [19] (Table 1). According to the KEGG pathway database, SLC4A4 is onlyinvolved in pancreatic and bile secretion, and FRS2 is only involved in theneurotrophin signalling pathway. Therefore we selected ACVR2A,FOXO1, IHH, STK4 and DUSP3 forfurther biomarker identification.

Bottom Line: DUSP3 levels were not significantly different between any groups.When the value of predictive probabilities was 0.449, the four proteins yielded a sensitivity of 68% and a specificity of 91%.Dynamic changes in ACVR2A, FOXO1 and IHH levels showed differential expression between survivors and non-survivors at all time points.

View Article: PubMed Central - PubMed

Affiliation: ‡Department of Respiratory Medicine, the Affiliated Beijing Tiantan Hospital of Capital Medical University, Beijing, 100050, China.

ABSTRACT
The goal of the present study was to identify novel protein biomarkers from the target genes of six serum miRNAs that we identified previously in patients with sepsis. The target genes were predicted by bioinformatics analysis; the levels of the respective proteins in the sera of patients with sepsis were detected by ELISA. ACVR2A (activin A receptor, type IIA), FOXO1 (forkhead box O1), IHH (Indian hedgehog), STK4 (serine/threonine kinase 4) and DUSP3 (dual specificity phosphatase 3) were predicted to be the targets of the six miRNAs, and their encoded proteins were used for biomarker identification. Levels of ACVR2A (P<0.01) and FOXO1 (P<0.01) were significantly different among normal controls, patients with sepsis, patients with severe sepsis and patients with septic shock. Furthermore, levels of ACVR2A (P=0.025), FOXO1 (P<0.001), IHH (P=0.001) and STK4 (P=0.001) were differentially expressed in survivors and non-survivors. DUSP3 levels were not significantly different between any groups. Conjoin analysis of the four differentially expressed proteins showed that the area under the curve of the predictive probabilities was 0.875 [95% CI (confidence interval): 0.785-0.965], which was higher than the SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. When the value of predictive probabilities was 0.449, the four proteins yielded a sensitivity of 68% and a specificity of 91%. Dynamic changes in ACVR2A, FOXO1 and IHH levels showed differential expression between survivors and non-survivors at all time points. On the basis of a combined analysis of the four identified proteins, their predictive value of 28-day mortality of patients with sepsis was better than the SOFA or APACHE II scores.

Show MeSH
Related in: MedlinePlus