Volume 22, Issue 5 (11-2019)                   J Arak Uni Med Sci 2019, 22(5): 32-43 | Back to browse issues page

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Mondanizadeh M, Moradi N, Amini R, Khansarinejad B, Mosayebi G. Bioinformatic Prediction of miRNAs Targeting APRIL and BAFF Genes in Chronic Lymphocytic Leukemia. J Arak Uni Med Sci 2019; 22 (5) :32-43
URL: http://jams.arakmu.ac.ir/article-1-6105-en.html
1- Molecular and Medical Research Center, Arak University of Medical Sciences, Arak University of Medical Sciences, Arak, Iran.; Department of Biotechnology and Molecular Medicine, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
2- Department of Biotechnology and Molecular Medicine, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
3- Molecular and Medical Research Center, Arak University of Medical Sciences, Arak University of Medical Sciences, Arak, Iran.; Department of Microbiology and Immunology, School of Paramedicine, Arak University of Medical Sciences, Arak, Iran.
4- Molecular and Medical Research Center, Arak University of Medical Sciences, Arak University of Medical Sciences, Arak, Iran.; Department of Microbiology and Immunology, School of Paramedicine, Arak University of Medical Sciences, Arak, Iran. , gmosayebi@yahoo.com
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Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults that appears to be caused by a defect in cell differentiation. CLL has various etiologic causes including genetic alterations and impaired intracellular signaling pathway. Therefore, the identification and evaluation of proteins involved in molecular signaling pathway in the CLL that changes their expression relative to the normal state can lead to the development of a new and effective therapeutic or diagnostic method. The two proteins of Apoptosis-Inducing Ligand (APRIL) and B-Cell Activating Factor (BAFF) play a role in the pathogenesis of this leukemia by affecting the Nuclear Factor Kappa B (NF-kB) signaling pathway. 
APRIL protein is significantly increased in the serum of patients with CLL, and by stimulating the NF-κβ pathway, ultimately inhibits apoptosis in B-cells. On the other hand, BAFF protein, by helping B-cell lymphocyte proliferation, ultimately inhibits B-cell apoptosis and cell progression to tumorigenesis and become cancerous. In recent years, researchers have found that some miRNAs can cause cells to become cancerous by reducing gene expression and gene silencing. This confirms the important potential of these molecular agents as biomarkers in the diagnosis, prognosis, progression, treatment and drug resistance of cancers including CLL. In this regard, considering the effect of miRNAs in regulating many cellular processes, the prediction of the prominent miRNAs targeting APRIL and BAFF transcripts in B-cell CLL patients was evaluated in the present study using specific and different bioinformatics programs.
Materials and Methods
This study is based on the bioinformatics theory. First, the sequences of APRIL and BAFF proteins were retrieved from the NCBI website. Then, by using bioinformatics programs of miRanda, TargetScan, miRWalk, DIANA and miRDB, the prediction of miRNAs targeting these genes was investigated. These programs have different algorithms. The miRanda program presents the results of bioinformatics assessments by providing an index called “miRSVR”, and the TargetScan program shows the results based on a factor called “Pct” (probability of conserved targeting) in humans and mammals, rats, worms, flies and frogs. Algorithm used in miRWalk software is based on prediction of miRNA binding site within complete sequences of all known genomes (even mitochondril genes).
The basis for prediction assessments in the DIANA program is an index called “miTG score” or precision score. In the miRDB database, the prediction score ranges from 50-100, and higher score shows the higher likelihood of miRNA binding to the target. Outputs from each program representing each miRNA score were then saved as an Excel file. Among the obtained data, miRNAs that the highest complementary to BAFF and APRIL genes were selected for the study. 
The results of the miRWalk program indicated that “miR-15a-5p”, “miR-500b-5p” and “miR-4803” were predicted and “miR-215” and “miR-192” were confirmed as BAFF gene targeters. The results of the DIANA program showed that the “miR-424” and “miR-497” targeted BAFF gene whose scores were 0.952 and 0.916, respectively. The results of the miRDB program reported that “miR-15a-5p”, “miR-497” and “miR-424” targeted BAFF gene with the highest scores. The results of the miRanda program showed that “hsa-miR-544” targets the BAFF gene. 
The results of the TargetScan program indicated that the APRIL gene is targeted by “miR-145-5p” and “miR-5195” with the highest score and the best binding conditions. The results of the miRanda program showed that “miR-185” with the highest score and more efficient binding can target the APRIL gene. Based on the results of the DIANA program, APRIL gene is targeted by “miR-6132” and “miR-185-5p” with the highest scores. According to the results of miRWalk program, numerous miRNAs both predicted and confirmed that were the targeters of APRIL gene. The results of miRDB database indicated that APRIL gene is targeted by hsa-miR-6716-5p and hsa-miR-4306 with the highest scores. Finally, “hsa-miR-145-5p” and “hsa-miR-185-5p” were identified as miRNAs targeting APRIL gene, and “hsa-miR-424” and “hsa-miR-497” were miRNAs targeting BAFF gene. They were suggested for the practical studies in future.
Bioinformatics is an important technique for managing large-scale biological data. Previous studies have indicated that mi-RNAs are involved in almost all physiological and pathological mechanisms. Similarly, despite demonstrating the aberrant expression of miRNAs in many diseases including cancers, these molecular agents can be used as potential biomarkers for both diagnosis and treatment. Therefore, it seems that the prediction of the miRNAs that target BAFF and APRIL gene can be an effective step in the diagnosis and treatment of B-cell CLL.
To our knowledge, this is the first time that bioinformatics programs of miRanda, TargetScan, miRWalk, DIANA and miRDB are used for the target prediction of miRNAs. Based on the results, we found out that “hsa-miR-145-5p” and “hsa-miR-185-5p” were the miRNAs targeting APRIL gene, and “hsa-miR-424” and “hsa-miR-497” were targeting BAFF gene. Since there is no specific study on the role of these miRNAs in the progression of B-cell CLL, the present study, as the first study, allows the introduction and assessment of miRNAs and new genes to help diagnose patients with this cancer.

Ethical Considerations
Compliance with ethical guidelines
This study obtained its ethical approval form the Research Ethics Committee of Arak University of Medical Sciences (Code: IR.ARAKMU.REC.1395.418).
This study extracted from a research proposal approved by the Arak University of Medical Sciences. We received financial support from the Deputy for Research and Technology of this university.
Authors' contributions
Conceptualization: Mahdieh Mondanizadeh and Ghasem Mosayebi; Investigation: Mahdieh Mondanizadeh, Niloofar Moradi and Razieh Amini; Review & editing: Mahdieh Mondanizadeh and Niloofar Moradi; Validation: Behzad Khansarinejad; Supervision: Ghasem Mosayebi.
Conflicts of interest
The authors declare no conflict of interest.
The authors would like to thank the Deputy for Research and Technology and the staff of the Laboratory of Molecular Microbiology and Virology at Arak University of Medical Sciences and Pastor Institute for their support and cooperation.
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Type of Study: Original Atricle | Subject: Basic Sciences
Received: 2019/07/8 | Accepted: 2019/08/27

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