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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 845-851

Study of serum microRNA-21 and alpha-fetoprotein in patients with hepatocellular carcinoma secondary to viral hepatitis


1 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission29-Jan-2020
Date of Decision23-Feb-2020
Date of Acceptance27-Feb-2020
Date of Web Publication18-Oct-2021

Correspondence Address:
David M Metry
Sohag
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_24_20

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  Abstract 


Objective
To evaluate the significance of plasma microRNA-21 (miR-21) level as a noninvasive marker for diagnosis and prognosis of hepatocellular carcinoma (HCC) and comparing the diagnostic accuracy of serum miR-21 with alpha-fetoprotein.
Background
In Egypt, HCC is the third most frequent cancer in men with more than 8000 new cases predicted. Early detection of HCC opens doors for various effective treatments such as surgical resection, radiofrequency ablation, and transplantation. Alterations of cancer tissue and circulating miRs have been shown in patients with HCC.
Patients and methods
This is a prospective study that was carried out at Cardiac and Digestive Institute, Sohag. The study group I included 20 patients with liver cirrhosis and HCC, aged 54–81 years, group II included 20 patients with liver cirrhosis only, aged 56–78 years, and group III included 20 healthy volunteers, aged 52–80 years.
Results
miR-21 was significantly higher in group I (18.69 ± 6.57) than group II (3.43 ± 2.0) and group III (1.0 ± 0.0), with highly statistically significant difference between the three groups (P < 0.001), and also, at area under the curve of 0.985, miR-21 had 95% sensitivity, 85% specificity, 86.4% positive predictive value, and 94.4% negative predictive value between group I and group II.
Conclusion
The current study showed that circulating miR-21 could be a novel early diagnostic and prognostic biomarker for detection of HCC in comparison with alpha-fetoprotein and abdominal ultrasound, which are not highly sensitive for early diagnosis of HCC, and hence eradication, and this is the novelty of this study.

Keywords: alpha-fetoprotein, diagnostic, hepatocellular carcinoma, liver cirrhosis, microRNA-21, prognostic


How to cite this article:
Ali AA, El-Hefnawy SM, Teima AA, Metry DM. Study of serum microRNA-21 and alpha-fetoprotein in patients with hepatocellular carcinoma secondary to viral hepatitis. Menoufia Med J 2021;34:845-51

How to cite this URL:
Ali AA, El-Hefnawy SM, Teima AA, Metry DM. Study of serum microRNA-21 and alpha-fetoprotein in patients with hepatocellular carcinoma secondary to viral hepatitis. Menoufia Med J [serial online] 2021 [cited 2024 Mar 28];34:845-51. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/845/328321




  Introduction Top


The hepatocellular carcinoma's (HCC) crucial risk factor that is responsible for its development is cirrhosis. The long periods of chronic liver illness are what causes cirrhosis and is categorized by a reduction in hepatocyte proliferation, representing the tiredness of the regenerative capacity of the liver [1].

HCC is the most common type of primary liver cancer and the third leading cause of cancer-related deaths worldwide [2].

HCC is considered one of the most violent diseases in the world, and is a major health problem in Egypt, representing 13% of all cancers in Egypt [3]. HCC is the second most common cancer in men [4].

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. According to the WHO, ~180 million individuals worldwide currently have HCV. Many of these infected people will go on to develop liver cirrhosis or liver cancer. Approximately 350 000 patients die each year owing to HCV and its related liver diseases [5].

In particular, chronic infections of hepatitis B and/or C can aid the development of HCC by repeatedly causing the body's own immune system to attack the liver cells, some of which are infected by the virus, whereas others merely bystanders [6].

Activated immune system inflammatory cells release free radicals, such as reactive oxygen species and nitric oxide reactive species, which in turn can cause DNA damage and lead to carcinogenic gene mutations [7].

Inflammation, necrosis, fibrosis, and ongoing regeneration characterize the cirrhotic liver and contribute to HCC development. In patients with hepatitis B virus (HBV), in whom HCC can develop in livers that are not frankly cirrhotic, underlying fibrosis is usually present, with the suggestion of regeneration. By contrast, in patients with HCV, HCC invariably presents, more or less, in the setting of cirrhosis. This difference may relate to the fact that HBV is a DNA virus that integrates in the host genome and produces HBV X protein that may play a key regulatory role in HCC development. HCV is an RNA virus that replicates in the cytoplasm and does not integrate into the host DNA [8].

MicroRNA-21 (miR-21) increased cell proliferation and suppressed apoptosis in a cancer xenograft model, further defining miR-21 as an oncogenic miR [9].

Among the deregulated miRs, miR-21 functions as an oncogene and its upregulation promotes malignant cell proliferation, invasion, and metastasis [10].

MiRs in serum or plasma have been considered as promising novel biomarkers for cancer diagnosis and prognosis [11].

The aim of this study is to evaluate the significance of plasma miR-21 level as a noninvasive marker for HCC diagnosis and prognosis, and also to compare the diagnostic accuracy of serum miR-21 with alpha-fetoprotein (AFP).


  Patients and methods Top


This is a prospective study and was carried out at Cardiac and Digestive Institute, Sohag, in the duration between April 2018 and January 2019.

The studied participants were divided into three groups. Group I included 20 patients with liver cirrhosis and HCC secondary to chronic viral hepatitis (B and C), and miR-21 level was measured before and after intervention for HCC. Group II included 20 patients with liver cirrhosis secondary to viral hepatitis (B and C) without HCC. Group III included 20 healthy volunteers as a control group. Exclusion criteria were patients with other malignancies other than HCC.

Disease severity was assessed by using the Child–Pugh score, which takes into account five conventional clinical (hepatic encephalopathy and ascites) and laboratory (albumin, prothrombin time, and bilirubin values) parameters. Each variable is assigned a score of 1–3 according to the grade of abnormality. Thus, patients with compensated cirrhosis (class A) receive a total score of 5–6, those with slightly moderate decompensated cirrhosis (class B) receive a score of 7–9, and those with severely decompensated disease (class C) receive a score of 10–15.

An informed consent was obtained from each participant before participation. The procedures applied in this study were approved by the ethical committee of the Faculty of Medicine, Menoufia University.

All patients and controls were subjected to the followings clinical studies: full medical history and complete clinical examination for all systems with stress on hepatobiliary system, especially ascites, jaundice, hepatic encephalopathy, abdominal pain, hematemesis, abdominal masses, lower limb edema. Laboratory studies included creatinine, liver function tests, complete blood count, erythrocyte sedimentation rate, serological markers (HCVAb–HbsAg), and serum AFP assay. Imaging studies included abdominal ultrasound for confirmation of liver cirrhosis and screening for HCC and triphasic computed tomography abdomen. All participants in this study did not receive any medications at the time of the study.

miR-21 expression was assessed by Taqman real-time PCR. MiR extraction was done from 100 μl of fresh serum samples. Total RNA including miR was extracted using miRNeasy isolation kit (QIAGEN, Hilden, Germany). RNA concentration and quality were assessed using a NanoDrop instrument (Thermo Scientific, Philadelphia, Pennsylvania, USA). RNA extract was stored at –80°C. Reverse transcription was performed using miScript II RT Kit (QIAGEN) for production of complementary DNA (cDNA). Each reaction was carried out on ice with a total volume of 20 μl. RT Master Mix was prepared as follows: 4 μl miScript HiSpec RT buffer (QIAGEN)+2 μl miScript Nucleics Mix (QIAGEN) +2 μl miScript Reverse Transcriptase (QIAGEN) +2 μl nuclease-free water (QIAGEN); the mixture was pipetted into each well. Then, 10 μl of miR extract was pipetted into each well. Incubation was done using 2720 thermal cycler Singapore Applied Biosystems for one cycle as follows: 37°C for 60 min, 95°C for 5 min for inactivation of reverse transcriptase. Produced cDNA was stored at −20°C till real-time PCR step. Real-time PCR was performed using miScript SYBR Green PCR Kit (QIAGEN). Before amplification, cDNA samples were diluted with nuclease-free water in a ratio of 1: 5 (4 μl cDNA + 16 μl of water). A total volume of 25 μl was applied, in the form of 12.5 μl of SYBR green Master Mix (QIAGEN), 3.5 μl of nuclease-free water, 4 μl of diluted cDNA, 2.5 μl of miScript universal primer (QIAGEN), and 2.5 μl of miScript primer assay (QIAGEN). The small nuclear SNORD (QIAGEN) was used for normalization. The following primers were used: mature miR-21 CCGUACCGUGAGUCAUAAUGCG and mature SNORD as a reference gene (miScript primer assay Kit; QIAGEN). Analysis of data was accomplished using real-time PCR instrument, software V.2.0.1, ABI7500 (Thermo Scientific).

Statistical analysis

Data were analyzed using Statistical Program for Statistical Program for Social Science, version 23.0 for Windows (SPSS Inc., Chicago, Illinois, USA). Quantitative data were expressed as mean ± SD. Median and range (minimum–maximum) were also calculated for quantitative data. Qualitative data were expressed as frequency and percentage. χ2 test also called Pearson's χ2 test or the χ2 test of association is used to discover if there is a relationship between two categorical variables. Analysis of variance test is a form of statistical hypothesis testing heavily used in the analysis of experimental data. Fisher exact test was used for significance, which was used in place of χ2 test in 2 by 2 tables, especially in small samples. Monte Carlo test allows examination of complex data more easily than advanced mathematics like integrals and matrix algebra. Kruskal–Wallis test is a nonparametric method for testing whether samples originate from the same distribution. It is used for comparing two or more independent samples of equal or different sample sizes. Post-hoc test consists of statistical analyses that were specified after the data were seen. Mann–Whitney U test is used to compare differences between two independent groups when the dependent variable is continuous but not normally distributed. Wilcoxon signed-rank test is a nonparametric statistical hypothesis test used to compare two related samples, matched samples, or repeated measurements on a single sample to assess whether their population mean ranks differ (i.e., it is a paired difference test).


  Results Top


This study was conducted on 20 newly diagnosed untreated HCC patients and 20 patients with liver cirrhosis owing to HCV and HBV infection presented to inpatients wards and outpatient clinic of Hepatology Department of Cardiac and Digestive Institute, Sohag, in the period from April 2018 and January 2019. In addition, 20 apparently healthy participants, matching regarding age and sex with the patients, served as a control group.

Participants included in the study were grouped as follows: group I included 20 newly diagnosed patients with HCC before receiving therapy with mean age of 66.60 ± 7.20 years. They were 10 males and 10 females. Group II included 20 patients with liver cirrhosis on top of HCV and HBV infection with a mean age of 65.15 ± 7.32 years. There were 11 males and nine females. Group III included 20 age-matched and sex-matched apparently healthy participants who served as a control group with mean age of 64.30 ± 8.14 years. They were nine males and 11 females.

The age in group I was 66.60 ± 7.20 versus 65.15 ± 7.32 in group II and 64.30 ± 8.14 in group III. In group I, 50% was male versus 55% in group II and 45% in group III. There was no statistically significant difference between both groups in age and sex distribution (P = 0.626 and 0.819, respectively) [Table 1].
Table 1: Comparison between the three studied groups regarding demographic data

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According to Barcelona Clinic Liver Cancer staging (n = 20), 60% of the cases had transarterial chemoembolization (TACE) and 40% had radiofrequency ablation. Overall, 85% had only one session and 10% had two sessions of TACE and only 5% had three sessions of TACE, with no residual detected by postintervention (s) triphasic computed tomography abdomen in 100% of cases [Table 2].
Table 2: Classification of group I (hepatocellular carcinoma cases) regarding the mode of intervention according to Barcelona Clinic Liver Cancer staging (n=20)

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MiR-21 was significantly higher in group I (18.69 ± 6.57) than group II (3.43 ± 2.0) and group III (1.0 ± 0.0), with significant difference among the three groups (P < 0.001) [Table 3].
Table 3: Comparison among the three studied according to microRNA-21 (fold change)

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In group I, there was a negative nonsignificant correlation between miR-21 and total bilirubin (r=−0.286 and P = 0.222) and international normalized ratio (r=−0.122 and P = 0.609). On the contrary, there was a positive nonsignificant correlation with albumin (r = 0.092 and P = 0.700). However, in group II, there was a negative nonsignificant correlation between miR-21 and total bilirubin (r=−0.286 and P = 0.296) and international normalized ratio (r=−0.117 and P = 0.625). On the contrary, there was a positive nonsignificant correlation with albumin (r = 0.104 and P = 0.661) [Table 4].
Table 4: Correlation between microRNA-21 (fold change) and total bilirubin, albumin, and international normalized ratio in group II (n=20)

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In group I, the AFP significantly decreased from 295.0 ± 349.4 to 11.34 ± 2.69 after intervention (0.002) and miR-21 also significantly decreased from 18.69 ± 6.57 to 2.57 ± 0.97 after intervention (<0.001) [Table 5].
Table 5: Comparison between alpha-fetoprotein and microRNA-21 (fold change) in group I (n=20) before and after intervention

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At area under the curve (AUC) of 0.985, miR-21 can significantly differentiated between group I and group II with 95% sensitivity, 85.0% specificity, 86.4% positive predictive value, and 94.4% negative predictive value [Table 6].
Table 6: Agreement (sensitivity, specificity) for microRNA-21 to diagnose group I from group II

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  Discussion Top


HCC is the most frequent form of primary liver cancer. It is the fifth most common cancer worldwide and the third cause of cancer mortality [12].

MiRs are small, noncoding RNA molecules that modify posttranscriptional gene regulation. They can suppress the protein expression of specific mRNAs through either degradation or translational inhibition. Alterations of miRs have been reported in a variety of human diseases, including malignancies [13].

In view of the previous observations, we conducted this study to evaluate the significance of plasma miR-21 level as a noninvasive marker for HCC and compare the diagnostic accuracy of serum miR-21 with AFP.

In this study, the age in group I was 66.60 ± 7.20 years versus 65.15 ± 7.32 years in group II and 64.30 ± 8.14 years in group III. In group I, 50% was male versus 55% in group II and 45% in group III. There was no significant difference between both groups in age and sex distribution (P = 0.626 and 0.819, respectively).

The present study found that among the patients with HCC, the males were more predominant than females, as men have a higher incidence of HCC than women owing to the stimulatory effects of androgen and the protective effects of estrogen. The anticarcinogenic effect in women is probably owing to estrogen-mediated inhibition of interleukin-6 production, a multifunctional cytokine largely responsible for the hepatic response to infections or systemic inflammation leading to a reduction in HCC risk in females.

In harmony with our study, a prospective cross-sectional study by Mohamed et al. [14] included 171 participants divided into group I, which comprised 57 patients with HCC; group II, which comprised 57 patients with liver cirrhosis; and group III, which comprised 57 healthy participants as a control group. Age was 55.9 ± 5.194, 54.88 ± 9.907, and 54.3 ± 6.34 in group I, group II, and group III, respectively. Most patients were male (64.91, 68.42, and 70.18, respectively), without a significant difference among the three groups regarding sex (P = 0.8289 and 0.5087, respectively).

In this study, regarding the main complaint, there was no significant statistical difference between the studied patient groups regarding abdominal pain, hematemesis, and refractory ascites for paracentesis but disturbed conscious level was statistically higher in group II (P = 0.047), as HCC associated with more deterioration of cases.

Moreover, the current study proved that there was no statistically significant association between type of viral infection and incidence of HCC, which agreed with Aljumah et al. [15].

In this study, miR-21 was significantly higher in group I (18.69 ± 6.57) than group II (3.43 ± 2.0) and group III (1.0 ± 0.0), with significant difference among the three groups (P < 0.001), and also, at AUC of 0.985, miR-21 had 95% sensitivity, 85% specificity, 86.4% positive predictive value, and 94.4% negative predictive value between group I and group II. MiR-221 contributed to hepatocarcinogenesis by dysregulating DNA damage-inducible transcript 4 and targeting the BMF gene relevant to apoptosis in HCC [16].

In agreement with the current study, Demerdash et al. [17] found the expression levels of plasma miR-21 were significantly higher in chronic hepatitis C (CHC) and HCC in comparison with healthy controls, with more significant increase in HCC compared with CHC group.

This was in agreement with Karakatsanis et al. [18], who reported that miR-21 was upregulated in HCC compared with healthy controls.

Moreover, the study by Borel et al. [19] examined 934 participants in four groups: healthy, chronic HBV, cirrhosis, and HBV-related HCC. Regardless of the stage of HCC, miR-21 accurately identified patients with HCC (AUC 0.89 with a specificity of 84% and a sensitivity of 82% for the validation set). This miR panel also accurately differentiated patients with HCC from healthy individuals and those with cirrhosis or chronic HBV. Additionally, miRs have a potential prognostic effect in patients with HCC.

Regarding biomarkers for HCC, Xu et al. [20] showed that serum circulating miR-21 was significantly increased in patients with HCC, which was also confirmed by Li et al. [21].

Connolly et al. [10] showed that miR-21 of human HCC tissue with HBV infection was increased compared with the nontumor liver tissue of the controls.

In disagreement with us, Sohn et al. [22] reported although the levels of serum miR-21 were generally higher in the HCC group compared with the CHB group, this difference did not reach statistical significance (P = 0.088).

Bihrer et al. [23] reported increased levels of miR-21 in sera from patients with CHC without HCC. Thus, the elevation of serum miR-21 levels in our patients with chronic hepatitis appears to be mainly associated with chronic hepatitis rather than HCC.

In this study, in group I, there was a nonsignificant difference in miR between cases with intermediate stage (A) (17.29 ± 7.32) and those with early stage (A) (20.78 ± 4.94) (P = 0.181).

This was in line with Tomimaru et al. [24] who examined the correlation between plasma miR-21 levels and TNM staging, and the results showed no significant differences in plasma miR-21 levels among patients with stages I, II, and IIIA.

Many studies have supported the hypothesis that miR-21 overexpression might promote HCC invasion and metastasis through direct or indirect mechanisms, and thus lead to poor prognosis [11].

These results are not consistent with the study done by Wang et al. [25] who revealed that circulating miR-21 levels were significantly higher in advanced HCC compared with early HCC groups.

Faltejskova et al. [26] showed that overexpression of miR-21 was associated with advanced clinical stage and lymph node metastasis in breast cancer, colorectal cancer, laryngeal squamous cell carcinoma, and HCC correspondingly. Furthermore, they indicated that patients with high miR-21 expression had poor prognosis and poor survival rates compared with patients with lower miR-21 expression.

Furthermore, Wang et al. [27] showed that in individuals with HCC, the high level of miR-21 expression correlated with cirrhosis and tumor stage.

Moreover, no significant correlation was found between the miRs and Child–Pugh grade in HCC group of patients according to study by El-Garem et al. [28].

Köberle et al. [29] stated that plasma miR expression reveals residual functional liver tissue in patients with end-stage liver disease.

Our results were supported by Riaz et al. [30] who reported that AFP response (>50% reduction) was seen in 26 (55%) of 47 patients treated with TACE (P = 0.12). AFP reduction of more than 20% and more than 90% from baseline was seen in 30 (64%) and 16 (34%) of TACE patients. Three (6%) TACE patients showed complete normalization of AFP levels after treatment (P = 0.11). The median pre-AFP and post-AFP was 1122 ng/ml (662–2151) and 601 ng/ml (201–1428), respectively (P = 0.015).

Moreover, these results are supported by Tomimaru et al. [24], as they found the plasma miR-21 level was measured in 10 patients before and after curative resection of HCC. Plasma miR-21 was also compared in other groups of 126 patients with HCC, 30 patients with chronic hepatitis, and 50 healthy volunteers. In the 10 patients with curative resection, miR-21 expression level in plasma samples was measured before (baseline) and after surgery. Plasma miR-21 expression level was significantly lower after surgery than at baseline (P = 0.0125).


  Conclusion Top


The current study showed that circulating serum miR-21 could be a novel early diagnostic and prognostic biomarker for detection of HCC in comparison with AFP and abdominal ultrasound, which are not highly sensitive for early diagnosis of HCC and hence eradication, and this is the novelty of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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