The existing evidence illustrates the key role of the extracellular miRNAs as potential diagnostic, prognostic and therapeutic biomarkers in ICU infections [22]. Sepsis is a life-threatening medical emergency and a major cause of mortality in ICU. A systematic review by Shen etal. indicated that the expression level of circulating miRNAs could be used as efficient biomarkers in diagnosis of sepsis [23]. In a recent study, Formosa and colleagues highlighted the critical role of miRNAs in sepsis pathogenesis. They showed the diagnostics, prognostic and therapeutic importance of miRNAs in sepsis [24]. Herein, we observed that miR-135a expression was unregulated in patients with sepsis compared with healthy controls. In current study, statistical analysis indicated that the level of circulating miR-135a could be used as valuable diagnostic and prognostic indicator for sepsis. However, there was no significant difference between the serum levels of miR-193 in the patients with sepsis and control group.
Several studies have conducted to evaluate the expression level and explore the molecular mechanism of miR-135a in human disease. Aberrant expression have highlighted the prognostic, value of miR-135a as a biomarker in diseases [25–27]. In a study by Zheng etal., they found that serum miR-135a levels were up-regulated significantly in sepsis patients compared with healthy control subjects. This study demonstrated that overexpression of miR-135a by transfection with lentiviruses (miR-135a mimic) into mice could aggravate sepsis-induced inflammation and myocardial dysfunction via activation of p38 MAPK/NF-κB pathway [28]. A comprehensive study by Cao etal., discovered that miR-135a play significant roles in cancer cell growth, migration and invasion. These findings pointed the great diagnostic, prognostic and therapeutic potential of miR-135a in different cancer types. In silico analyses and experimental validations revealed that miR-135a could activate several signaling pathways, including the PI3K/AKT pathway, JAK2/STAT3 pathway, p38 MAPK/NF-κB pathway [29]. Mir-135a has also diverse roles in the pathogenesis of non-cancerous disorders in human such as myocardial ischemia, focal segmental glomerulosclerosis and atherosclerosis through different mechanisms [30]. With this approach, we evaluated the circulating levels of miR-135a in the patients with sepsis in comparison with healthy controls. Our findings supported that miR-135a could be beneficial as the diagnostic and prognostic biomarker for sepsis patients.
Comparative genome analysis by sequence alignment showed that mir-193 is highly conserved across species [31]. In normal cells, miR-193 seemed to target different genes and subsequently, limit cell proliferation and cell cycle progression. The expression of miR-193 can be regulated by transcription factors and epigenetic mechanisms. Mir-193 is involved in many biological process of cells, such as cell proliferation, migration. The results of numerous piece of research have demonstrated that miR-193 dysregulation contribute mainly as a tumor suppressor in both liquid and solid tumors [32, 33]. Two separate studies showed the aberrant expression of miR-193 in patients with schizophrenia and Parkinson's disease [34, 35]. Based on an in vitro study, DNA hypermethylation of the promoter region in miR-193 causes reducing the miRNA expression and suppression of important signaling pathways in cancers [36]. Other studies also show that miR-193 family play the critical roles in the pathological mechanisms of cardiovascular diseases [37–39]. Solexa sequencing followed by quantitative reverse transcriptase polymerase chain reaction assays showed that miR-193 was significantly differentially expressed between survivors and non-survivors of sepsis. This study introduced miR-193 as a prognostic biomarker for sepsis [40]. Wang etal. showed the significant differences in the expression level of miR-193 in patients with sepsis in comparison with healthy controls [41]. The recent prospective observational study by the droplet digital PCR showed demonstrable significant differences in expression level of miR-193 between patients with septic intensive care, and non-septic intensive care [42]. MiR-193 play critical role in cell growth and inflammation, as well as survival by directly targeting the signal transducer and activator of transcription 3 (STAT3) [43, 44]. Two separate studies reported that myocardial injury may occur by targeting STAT3 expression in mice with sepsis [45, 46]. Against this background, we evaluated the circulating level of miR-193 in sepsis patients and healthy control. However, according to our data, there was no statistically significant association between miR-193 expression level between patients with sepsis and age/ gender matched controls. Benz et al. showed the high variability in the expression level of U6 in human patients as well as mice model of polymicrobial sepsis [47]. Therefore, the unstable level of U6 between different individuals and during diseases has limited the potential use of U6 for normalization of circulating miRNA analysis. For that reason, using of U6 as a qPCR housekeeping may limit validity and reproducibility and explain the contradictory findings in the expression level of miR-193 in patients with sepsis and controls in different studies. In the present study, GAPDH was used as the reference gene for normalizing qRT-PCR analysis. Despite present limitation, more studies are necessary to determine the prognostic role of circulating miR-193 in sepsis.