Predictive value and clinical significance of miR-186-5p in the development of esophageal varices in cirrhosis patients
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Xinbo Chen
,
Wei Li
und
Bao Wang
Abstract
Objectives
Timely prediction of esophageal varices (EV) in cirrhotic patients is an effective step in the clinical management of cirrhotic patients. The aim of this study was to investigate the potential of microRNA-186-5p (miR-186-5p) a risk factor for EV in cirrhotic patients.
Methods
Serum miR-186-5p was detected by RT-qPCR assay. ROC curve was employed to assess the possibility of miR-186-5p in the diagnosis of cirrhosis and EV. Moreover, the pathological mechanism of miR-186-5p target genes in EV was elucidated by GO and KEGG analysis.
Results
miR-186-5p was downregulated in cirrhotic patients and had high diagnostic value in identifying cirrhosis. Meanwhile, miR-186-5p expression was decreased in EV patients with cirrhosis. Downregulation of miR-186-5p may sensitively predict the occurrence of EV in cirrhotic patients. Moreover, pathomechanism analysis elaborated that miR-186-5p downstream target genes were highly accumulated in regulation of mRNA processing, endoplasmic reticulum-Golgi intermediate compartment, protein serine/threonine kinase activity,and autophagy-animal.
Conclusions
miR-186-5p has high accuracy in predicting cirrhosis occurrence and identifying EV.
Introduction
Cirrhosis is a chronic liver disease, in which liver cells are gradually replaced by fibrous tissue under the influence of long-term inflammation and injury to the liver, leading to abnormal changes in liver structure and function [1]. Esophageal varices (EV) are conditions in which the internal esophageal veins become distended and distorted due to obstruction of blood flow, which are common complications in patients with cirrhosis [2], 3]. As a manifestation of blood return disorders caused by liver disease, rupture bleeding from EV is the leading cause of death in patients with cirrhosis [4]. Variceal bleeding was reported to occur in 4 % of cirrhotic EV patients and has a mortality rate of more than 20 % within 6 weeks and an annual mortality rate of more than 80 % [5]. Therefore, identification and management of EV is critical for mitigating the risk of bleeding in patients with cirrhosis.
In the current clinical application, gastrointestinal endoscopy is the most commonly recommended method for the diagnosis of EV [2]. Although in recent years, scholars have proposed a large number of noninvasive methods for the diagnosis of EV, however, they cannot completely replace the use of gastrointestinal endoscopy in clinical practice at this stage. It is worth noting that upper gastrointestinal endoscopy is an invasive examination modality with disadvantages such as high cost and poor patient acceptance [6]. Based on this, the exploration of non-invasive prediction methods for EV patients is still a research hotspot in the future.
Serological indicators refer to a method to assess human health by detecting certain chemicals or biomarkers in blood, which can provide information about the body’s metabolism, immune system function, liver function and nutritional status [7]. In patients with cirrhosis, serologic markers can be an important indicator for assessing liver function and the degree of portal hypertension, thereby helping to monitor the development of esophageal varices and prevent the occurrence of related complications. Meanwhile, the application of microRNA (miRNA) in human diseases has gradually become a current research trend [8]. miR-186-5p is positioned on chromosome 1p31.1 and was observed to be downregulated in numerous types of tumors [9]. miR-186-5p was revealed to mediate the regulation of cardiac microvascular endothelial cells damage and the progression of coronary artery disease [10]. In hepatic ischemia/reperfusion injury, miR-186-5p was also thought to accelerate the apoptosis of liver cells by binding YY1 [11]. Additionally, miR-186-5p was found to act as a suppressor in acute myocardial infarction, renal fibrosis, and sepsis-acute lung injury [12], [13], [14]. Based on the potential of miR-186-5p as a therapeutic target in different diseases, we hypothesized that it may also serve as a risk marker in EV patients.
By collecting clinical data of patients with cirrhosis, this study further evaluated the relationship between noninvasive serological indicators and patients with cirrhosis of EV, and provided a new direction for the prediction and disease evaluation of EV patients through the detection and diagnostic analysis of serum miR-186-5p expression.
Materials and methods
Inclusion of patients
There are 140 patients with cirrhosis who were hospitalized in the Department of Gastroenterology of Shengli Oilfield Central Hospital (No. 2021-08, July 14, 2021)were enrolled in the present study during the period from January 1, 2022, to December 31, 2023. And 136 healthy individuals who underwent physical examination in the hospital during the same period were also enrolled in the study. All subjects were informed about the study and voluntarily participated in the whole process. In addition, informed consent has been obtained from the participants involved.
Inclusion criteria of patients with cirrhosis: (1) patients were diagnosed with cirrhosis by clinical manifestations, past medical history, serological examination, and imaging examination. (2) All patients underwent serological tests such as blood routine, liver function, coagulation four indices, renal function, and alpha-fetoprotein in our hospital. (3) All patients underwent upper gastrointestinal endoscopy within 1 week after admission to confirm the presence or absence of EV in the endoscopy center of our hospital. Patients were excluded if they met the following criteria: (1) combined with primary liver cancer, hematological diseases or hepatic portal vein system thrombosis. (2) Previous use of medications that may affect portal pressure, such as B-blockers. (3) Combined with a history of gastrointestinal bleeding within 2 weeks or drug-induced liver injury. (4) Patient has a history of surgical procedures such as splenectomy, esophageal variceal ligation or sclerotherapy, and transjugular intrahepatic portosystemic shunt.
A power analysis was conducted using G*power 3.1 to determine the required sample size. Based on an effect value of 0.5, a significance level of 0.05, and a power of 0.95, the analysis indicated that the study required a minimum sample size of 88 participants. This study had sufficient sample size for analysis.
General information collection
The general clinical data of the included patients were obtained from the electronic medical record management system of Shengli Oilfield Central Hospital. Venous blood was collected from the patients in the fasting state. The centrifuge (Eppendorf, USA) was set at 3,000 r/min 4 °C, and serum samples were separated for 10 min and stored in an ultra-low temperature refrigerator (Haier, China) at −80 °C. The liver function indexes, coagulation routine indexes and renal function indexes of the patients were examined by a total dry chemistry biochemical analyzer (ITROS350 biochemical analyzer; Johnson & Johnson, USA).
Detection of miR-186-5p expression
Trizol reagent (1 mL) was added to serum samples (100 µL) and chloroform (200 µL) was added after thorough mixing. The upper aqueous phase was aspirated after centrifugation, and an equal volume of isopropanol was added to precipitate the RNA. The quality and integrity of the RNA were verified. The cDNA corresponding to miR-186-5p was synthesized by TaqMan microRNA reverse transcription kit (Invitrogen, USA). The reaction system was prepared using the SYBR®Premix Ex Taq kit (TaKaRa, Japan) using cDNA as template and amplified on a PCR system (BIO-RAD, USA). Data were processed using the 2−ΔΔCt method using U6 as an internal reference index. The primer sequences are as follows: miR-186-5p forward 5′-GATCCGAGCCATGCTTATGCTA-3′ and reverse 5′-GGCCGCCCAGGTATATGGC-3′; U6 forward 5′-GCTTCGGCAGCACATATACTAA-3′ and reverse 5′-CTTCACGAATTTGCGTCAT-3′. Three replicates were performed for each set of experiments.
Statistical analysis
The data were statistically analyzed by SPSS 20.0 and Graphpad 10.0 softwares. Measurement data were expressed as mean ± SD, and Student’s t-test was used between groups. Counting data were expressed by the number of cases and percentage (n/%), chi-square test was used for comparison between groups following Bonferroni correction. The diagnostic value of miR-186-5p for EV was evaluated using the receiver operating characteristic curve (ROC) and the area under the curve (AUC). p<0.05 was considered statistically significant.
Results
Baseline data of the subjects
In Table 1, there were a total of 276 subjects were enrolled. The control group consisted of 136 individuals including 78 males (57.35 %) and 58 females (42.65 %) with a mean age of 55.61 ± 10.14 years. The cirrhosis patients group included 73 males (52.14 %) and 67 females (47.86 %), with a total of 140 participants, with a mean age of 55.49 ± 9.31 years. The results indicated no obvious differences between the two groups (p>0.05).
Baseline data of the subjects.
| Variables | Subjects (n=276) | χ2/t | df | p-Value | |
|---|---|---|---|---|---|
| Control (n=136) | Cirrhosis patients (n=140) | ||||
| Gender | 0.756 | 1 | 0.385 | ||
| Male | 78 (57.35) | 73 (52.14) | |||
| Female | 58 (42.65) | 67 (47.86) | |||
| Age, years | 55.61 ± 10.14 | 55.49 ± 9.31 | 0.100 | 274 | 0.920 |
| Etiology of liver diseases, n (%) | |||||
| Hepatitis B virus | – | 106 (75.71) | |||
| Hepatitis C virus | – | 27 (19.29) | |||
| Alcohol | – | 5 (3.57) | |||
| Others | – | 2 (1.43) | |||
| Child-Pugh classification | |||||
| A | – | 67 (47.86) | |||
| B | – | 60 (42.86) | |||
| C | – | 13 (9.28) | |||
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EV, esophageal varices. All data were presented as mean ± standard deviation or n.
Additionally, hepatitis B virus and hepatitis C virus are the main causes of cirrhosis, and alcohol and autoimmune diseases can also cause cirrhosis. As for the Child classification of patients, 67 cases (47.86 %) were in Child grade A, 60 cases (47.9 %) were in Child grade B, and 13 case (9.28 %) were in Child grade C.
Analysis of serological indexes of patients
The cirrhosis patients were classified into the no esophageal varices group (No-EV; n=36) and esophageal varices group (EV; n=104) by the results of upper gastrointestinal endoscopy performed. The comparison of clinical indices between the No-EV and EV patient groups revealed no significant differences in terms of age, gender, etiology, and child classification (p>0.05). Meanwhile, there were no significant changes in alanine aminotransferase (ALT), alanine transaminase (AST), total bilirubin (TBIL), creatinine (Cr), and international normalized ratio (INR) levels in the EV group compared to the No-EV group (p>0.05). However, the levels of prothrombin time (PT; p<0.001), albumin (ALB; p<0.001), and platelet count (p=0.046) were significantly different (Table 2).
Comparison of serological indexes in each group.
| Indicators | Cirrhosis patients (n=140) | χ2/t | df | p-Value | |
|---|---|---|---|---|---|
| No-EV (n=36) | EV (n=104) | ||||
| Age, years | 53.39 ± 9.21 | 54.89 ± 8.50 | −0.896 | 138 | 0.372 |
| Gender, n/% | 0.454 | 1 | 0.500 | ||
| Male | 20 (55.56) | 51 (49.04) | |||
| Female | 16 (44.44) | 53 (50.96) | |||
| Etiology of liver diseases, n (%) | 1.521 | 3 | 0.739 | ||
| Hepatitis B virus | 26 (72.22) | 80 (76.92) | |||
| Hepatitis C virus | 8 (22.22) | 19 (18.27) | |||
| Alcohol | 2 (5.56) | 3 (2.88) | |||
| Others | 0 (0) | 2 (1.93) | |||
| Child-Pugh classification | 2.472 | 2 | 0.290 | ||
| A | 18 (50.0) | 49 (47.32) | |||
| B | 17 (47.92) | 43 (41.96) | |||
| C | 1 (2.08) | 12 (10.72) | |||
| Laboratory indicators | |||||
| ALT, U/L | 52.38 ± 12.34 | 51.17 ± 14.16 | 0.457 | 138 | 0.648 |
| AST, U/L | 83.80 ± 27.22 | 74.54 ± 31.00 | 1.592 | 138 | 0.114 |
| TBIL, mg/dL | 5.83 ± 3.87 | 6.82 ± 3.87 | −1.344 | 138 | 0.190 |
| Cr, μmoI/L | 64.46 ± 21.01 | 68.01 ± 22.36 | −0.832 | 138 | 0.407 |
| PT, sec | 13.09 ± 3.73 | 15.94 ± 2.68 | −4.951 | 138 | <0.001 |
| INR | 1.55 ± 0.48 | 1.49 ± 0.59 | 0.552 | 138 | 0.582 |
| ALB, g/dL | 3.46 ± 0.61 | 2.99 ± 0.56 | 0.433 | 138 | <0.001 |
| Platelet count, 1 × 109/L | 129.34 ± 76.70 | 100.90 ± 55.49 | 2.389 | 138 | 0.046 |
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EV, esophageal varices; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALB, albumin; TBIL, total bilirubin; PT, prothrombin time; Cr, creatinine; INR, international normalized ratio. All data were presented as mean ± standard deviation or n.
Expression of miR-186-5p in cirrhosis
The data set GSE250272 was employed to examine the levels of miRNAs before and after treatment in patients with cirrhosis, and the downregulated miR-186-5p in cirrhosis was screened out (Figure 1A). Furthermore, PCR detection of serum samples in each group showed that the miR-186-5p expression in patients with cirrhosis was lower than the healthy control (Figure 1B).
Expression and diagnostic value of miR-186-5p in cirrhosis. (A) miR-186-5p with decreased expression in cirrhosis was screened using the dataset GSE250272. (B) miR-186-5p was reduced in cirrhotic patients. (***p<0.001). (C) The AUC for miR-186-5p to differentiate between healthy individuals and cirrhotic patients was 0.881.
Construction of ROC curve based on miR-186-5p expression showed that the sensitivity and specificity of miR-186-5p for diagnosing cirrhosis patients were 82.9 % and 84.6 %, with an AUC of 0.881 (Figure 1C), suggesting that dysregulation of miR-186-5p may be used for the identification of cirrhosis patients.
Predictive potential of miR-186-5p for EV
miR-186-5p expression was revealed to be poorly expressed in the EV group compared with the No-EV group (Figure 2A). Multivariate logistic analysis and forest plot confirmed that miR-186-5p served as an independent predictor for EV in cirrhosis patients (p<0.001, OR=7.134 (2.774–18.345); Figure 2B). In addition, miR-186-5p also had a high predictive ability for the diagnosis of EV patients (AUC=0.919, sensitivity=82.7 %, specificity=86.1 %; Figure 2C).
Role of miR-186-5p in EV. (A) Levels of miR-186-5p in EV group was lower than in No-EV group (***p<0.001). (B) miR-186-5p was a risk indicator for EV in cirrhosis patients (p<0.001). (C) Diagnostic ability of miR-186-5p in No-EV group and EV group (AUC=0.919).
Furthermore, we evaluated the efficacy of miR-186-5p with existing clinically used non-invasive biomarkers in the prediction of EV, and showed that miR-186-5p had a significantly higher AUC than Platelet count (AUC=0.614) and APRI (AUC=0.710), and the sensitivity of the combined diagnostic was stronger (AUC=0.928, sensitivity=87.5 %, specificity=83.3 %; Supplementary Figure 1 and Table 1).
Potential pathological mechanisms of miR-186-5p in EV
The possible downstream targets of miR-186-5p were predicted by by TargetScan, miRDB, starbase, and miRWalk online databases and the Venn diagram was drawn in Figure 3A and Supplementary Table 2. miR-186-5p target genes accumulate in multiple biological processes related to EV, such as regulation of mRNA processing, regulation of mRNA splicing, via spliceosome, and regulation of nucleocytoplasmic transport (Figure 3B). Cellular component analysis confirmed that miR-186-5p target genes were significantly enriched in endoplasmic reticulum-Golgi intermediate compartment, nuclear periphery, nuclear pore and dendrite cytoplasm (Figure 3C). Meanwhile, the downstream target genes of miR-186-5p function on protein serine/threonine kinase activity, protein serine/threonine/yrosine kinase activity, and chromatin DNA binding (Figure 3D). The target genes of miR-186-5p were prominently expressed in autophagy-animal, longevity regulating pathway, and cAMP signaling pathway upon KEGG pathway analysis (Figure 3E).
Analysis of the pathogenesis of miR-186-5p target genes in EV. (A) Venn diagram of miR-186-5p downstream targets. (B–D) GO analysis of miR-186-5p target genes. (E) KEGG pathway analysis of miR-186-5p target genes.
Discussion
Portal hypertension in cirrhosis leads to obstruction of the portal vein, which in turn leads to the formation of EV [15]. Severe esophageal varices can rupture and bleed with acute onset, rapid progress, and difficulty in hemostasis, which seriously threatens the life and health of patients [16]. Therefore, early screening of EV is of great significance to the treatment of cirrhosis patients.
By analysing the clinical data of the included healthy individuals and patients with cirrhosis, age and gender were not significantly different in the two groups, suggesting that the occurrence of cirrhosis is not closely related to the age and gender of patients. Furthermore, patients with cirrhosis were divided into two groups based on whether or not they developed EV, and hepatitis B virus (HBV) and hepatitis C virus (HCV) were the main causes of EV in cirrhosis patients in this study. Both HBV and HCV can cause acute or chronic hepatitis, and gradually lead to liver fibrosis and cirrhosis with the occurrence of infection [17]. In addition, during the course of cirrhosis, the liver’s ability to synthesise coagulation factors is affected, especially when EV occurs, and the synthesis of coagulation factors is reduced, which in turn causes prolongation of the PT [18], which is consistent with our findings. Meanwhile, the EV in patients with cirrhosis may be the splenic function, and cause the spleen vein is blocked, thus affecting the generation of platelets [19]. An increase in the degree of EV implies severe damage to the liver cells, which in turn causes a decrease in ALB levels [20], 21]. Peng et al. proposed that TBIL, INR, and ALB are biological indicators of liver injury and that ALB levels are reduced in patients with severe liver injury. Similarly, we noted that ALB and platelet counts were downregulated in EV patients. The latest studies have shown that the decrease of ALB and Platelet count can be used as clinical indicators to predict EV [22], 23], implying that our results have certain reference value.
Low expression of miR-186-5p was demonstrated in a variety of diseases [24], 25]. This study confirmed the decreased miR-186-5p in cirrhosis through bioinformatics screening and PCR experiments, and miR-186-5p showed high sensitivity and specificity in the identification of cirrhosis. Furthermore, miR-186-5p also showed a decreasing trend in EV patients with cirrhosis, and it was elucidated as a risk factor for EV development by binary logistic regression analysis. The drawn ROC curve clarified that miR-186-5p showed high diagnostic potential in distinguishing the EV group from the No-EV group. Among the already existing evidence, Ren et al. recognised that miR-744 was reduced in cirrhosis models and inversely proportional to the severity of the disease, suggesting that miR-744 is a reliable biological factor for cirrhosis [26]. Meanwhile, miRNAs were demonstrated effective diagnostic and therapeutic functions in portal hypertension [27]. Moreover, we realized that the sensitivity and specificity of miR-186-5p were much higher than those of Platelet count and APRI by comparing the predictive performance of the existing non-invasive markers with miR-186-5p, which can be used in combination in clinical diagnosis. These results implies that miR-186-5p have certain diagnostic potential in predicting cirrhosis patients with EV.
Mechanistically, GO and KEGG analysis revealed the potential role of miR-186-5p in biological functions and metabolic pathways. At the biological engineering level, miR-186-5p is involved in the regulation of mRNA processing, regulation of nucleocytoplasmic transport, and regulation of mRNA splicing via spliceosome. At the level of cellular components, miR-186-5p functions mainly in the endoplasmic reticulum-Golgi intermediate compartment, and some miR-186-5p participates in the regulation and processing in the nuclear periphery and nuclear pore. In molecular function, miR-186-5p was enriched in protein serine/threonine kinase activity, protein serine/threonine/tyrosine kinase activity and chromatin DNA binding. Meanwhile, KEGG analysis elucidated that miR-186-5p plays a role in the cAMP signaling pathway and the longevity regulating pathway. In previous studies of fatty liver, alternative RNA splicing enriched mRNA processing and spliceosome regulation [28]. In addition, the molecular function of the miR-186-5p target gene is related to protein serine/threonine kinase activity, protein serine/threonine/yrosine kinase activity, and chromatin DNA binding. The target genes of four miRNAs may be associated with protein phosphorylation, as also demonstrated by Lin et al. in their study of prognostic indicators of lung adenocarcinoma [29]. This suggested a potential role for miR-186-5p in the biological and metabolic pathways of EV in cirrhotic patients. Abnormal levels of miR-186-5p combined with downstream LOX-1 exacerbated atherosclerosis in patients with acute myocardial infarction in a study by Ding et al. [12]. Additionally, miR-186-5p targeting FOXK1 and CXCL1 was also shown to exert regulatory potential in osteosarcoma and liver injury [30], 31]. In subsequent studies, we aim to investigate the functional roles and molecular mechanisms of miR-186-5p downstream targets in EV.
Through the non-invasive detection of miR-186-5p level, the high-risk population of EV can be identified early in patients with liver cirrhosis, so as to carry out endoscopic screening and intervention in advance, and develop individualized treatment plans, thereby reducing the mortality of patients and improving the quality of life of patients. However, we must acknowledge that although these findings confirm the high diagnostic value of miR-186-5p in predicting the occurrence of EV, they still cannot replace the traditional invasive examination. In addition, this study also has the shortcomings of small sample size and single-center study, which affects the generality of the study results to a certain extent.
Conclusions
In summary, downregulation of miR-186-5p provides a certain guiding in predicting cirrhosis occurrence and identifying EV.
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Research ethics: The study protocol was approved by The Ethics Committee of Shengli Oilfield Central Hospital (No. 2021-08, July 14, 2021) and followed the principles outlined in the Declaration of Helsinki.
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Informed consent: In addition, informed consent has been obtained from the participants involved.
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Author contributions: Concept – X. B. C., W. L.; design – B. W.; supervision – X. B. C., W. L., B. W.; resources – X. B. C., W. L., B. W.; materials – X. B. C., W. L., B. W.; data collection and/or processing – X. B. C., W. L., B. W.; analysis and/or interpretation – X. B. C., W. L., B. W.; literature search – X. B. C., W. L., B. W.; writing manuscript – X. B. C., W. L., B. W.; critical review – X. B. C., W. L., B. W.
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Use of Large Language Models, AI and Machine Learning Tools: No.
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Conflict of interest: The authors declare that they have no competing interests.
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Research funding: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
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Data availability: Corresponding authors may provide data and materials.
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Supplementary Material
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