1. Introduction

cervical Cancer (CC) is the third most common malignancy in the women, the main cause of which is Human Papillomavirus (HPV) [3, 6]. The E6 and E7 genes in the HPV genome are known as viral oncogenes and play an important role in its tumorigenesis [9]. At present, methods available for screening CC are not capable of detecting the disease at an early stage [13]. Therefore, it is important to identify new and non-invasive biomarkers with high sensitivity and specificity for early detection of this cancer. Moreover, miRNAs are found in different tissues with variable expression, and their expression profiles change in the disease state [30]. These molecules can be used as novel biomarkers in diagnosis and treatment of various cancers [31]. Therefore, in the present study, miRNAs targeting the two oncogenes E6 and E7 of human papillomavirus (types 16 and 18) were studied in CC by bioinformatics tools.

2. Materials and Methods

First, the E6 and E7 genes sequences were obtained for both human papillomavirus types 16 and 18 using the NCBI database (http://www.ncbi.nlm.nih.gov/gene). Then, the most appropriate miRNAs targeting E6 and E7 genes were selected using various bioinformatics databases including Miranda, Vir-Mir, Targetscan, miRNA path, miRBase and RNA22. The sequences of predicted miRNAs were retrieved from miRBase database (www.mirbase.org). Moreover, the complementary relationship between miRNA and target gene based on P-value was determined by the RNA22 bioinformatics database (http://cm.jefferson.edu/rna22/Interactive/). The P value represents the random possibility of binding the target miRNA. That is, a lower P represents a greater chance of binding to the target gene.

3. Results

The bioinformatics analyzes indicated that Miranda, Vir-Mir, Targetscan and miRNA path databases were not able to predict miRNAs targeting E6 and E7 viral genes. The obtained results of miRBase and RNA22 databases demonstrated that four miRNAs including miR-92a-5p (P=7.51e-2), miR-195-3p (P=2.24e-1), miR-34a-5p (P=2.73e-1) and miR-155-5p (P=4.95e-2) are the miRNAs that target E6 and E7 genes (Table 1).

Among these miRNAs, miR-155-5p (P=4.95e-2) and miR-92a-5p (P=7.51e-2) are likely the specific target miRNAs for the E6 and E7 genes, respectively.

4. Discussion 

Numerous studies have shown that miRNAs are closely linked to various diseases, including cancer, because these molecules are involved in all biological processes, including cell growth and differentiation, cell cycle regulation, stress response, and apoptosis [16]. The structure and function of miRNAs suggest that the expression of many miRNAs in cancerous tissues changes abnormally compared to normal tissue [30]. Therefore, changing the expression profile of miRNAs can be used as biomarkers to diagnose a wide range of diseases [31]. At present, various methods such as microarray analysis, In Situ Hybridization (ISH), northern blot, and Real Time PCR are used to measure miRNAs. This method is time consuming and expensive, while bioinformatics tools are effective and low-cost methods that can be used to predict the interaction between miRNAs and target genes [32, 33]. 

In this study, considering the oncogenic role of E6 and E7 genes of human papillomavirus in CC, different bioinformatics databases were used to identify and predict the miRNAs targeting these genes. Bioinformatics results indicated that four miRNAs including miR-92a-5p, miR-195-3p, miR-34a-5p and miR-155-5p are the miRNAs that target E6 and E7 genes. Among these miRNAs, miR-155-5p and miR-92a-5p are likely the specific target miRNAs for the E6 and E7 genes, respectively. Other studies have shown that eight miRNAs, including miR-16, miR-25, miR-92a, miR-378, miR-22, miR-27a, miR-29a, and miR-100, have the highest accuracy for CC detection, and they can be used to differentiate between CC patients and healthy individuals [39].

5. Conclusion

Our results suggest that miR-155-5p and miR-92a-5p can be a suitable candidate for in vitro studies in CC patients. These miRNAs can be used as diagnostic biomarkers if they have a change in expression in CC patients compared to healthy individuals.

Ethical Considerations

Compliance with ethical guidelines

This study approved in Ethical Committee of Arak University of Medical Science (Code: IR.ARAKMU.REC.1396.296).

Funding

The present paper was extracted from the MSc thesis of the first author, Department of Biotechnology and Molecular Medicine, School of Medicine, Arak University of Medical Sciences.

Authors' contributions

All authors contributed in preparing this article.

Conflicts of interest

The authors declared no conflict of interest.

Acknowledgements

The authors would like to thank Research Assistance of Arak University of Medical Sciences due to its financial grant and support of this study.


 

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