Expression profile of cellular microRNAs and their potential role in cervical cancer

Abstract

Background. Cervical cancer (CC) is the fourth leading cause of cancer-related morbidity and mortality among women. Despite the established etiologic factor of cervical cancer, especially high-risk human papillomavirus (HPV, human papillomavirus) and available vaccine prophylaxis, the issue persists both in understanding the mechanism of HPV-associated carcinogenesis and in developing new approaches for diagnosis and treatment of cervical cancer. Epigenetic regulation of gene expression by means of microRNAs plays an important role in the pathogenesis of cervical cancer. Therefore, the search for new differentially expressed microRNAs in order to reveal new mechanisms of HPV-associated transformation of tumor cells is of high priority.

AIM: To explore microRNAs with differentiated expression in the cervical cancer tissue and to assess the functional potential of their detection in silico.

MATERIALS AND METHODS: The spectrum of microRNAs characterizing by modified expression in the tumor tissue of HPV16-positive squamous cell carcinomas of the cervix was determined using NGS sequencing (Next Generation Sequencing) of tumor tissue and of apparently unchanged adjacent epithelium obtained with the use of microdissection. Potential target genes of the investigated microRNAs were identified using MirTargetLink, Tarbase v9.0, and LinkedOmics services. Gene Set Enrichment Analysis was performed using Metascape. The relations between the level of microRNA expression and clinical SCC features (according to TCGA data, CESC sample) were searched using USCS Xena service.

RESULTS: NGS-sequencing of paired HPV16-positive specimens of tumor tissue and normal cervical tissue resulted in the identification of 42 differentially expressed microRNAs. Specifically, the levels of 22 microRNAs in the tumor tissue were higher than in the apparently normal adjacent epithelium, while 20 microRNAs demonstrated lower levels in the tumor specimens. Analysis of the potential targets of significant microRNAs revealed multiple functional gene categories, potentially involved in carcinogenesis as well as an association with clinical features. We showed that increased expression levels of microRNA-20b in the tumor tissue correlated with the risk of distant metastases, whereas the lower levels of microRNA-218-1 and microRNA -218-2 were associated with unfavorable prognosis of disease. With regard to microRNA-363, -615, and -769, their increase in cervical cancer was described for the first time, and the potential targets and signaling pathways associated with THEIR EXPRESSION LEVELS WERE IDENTIFIED.

CONCLUSION: The search for differentially expressed microRNAs in cervical cancer has revealed a spectrum of microRNAs with potentially important role in the process of malignant transformation and persistence of tumor phenotype. In addition to microRNAs demonstrating functional characteristics described in the world literature, we found microRNAs that play an unknown role in cervical cancer. In this relation, the potentially relevant targets were identified that could be helpful in understanding the mechanisms of carcinogenesis. The data obtained may form the basis for the development of new approaches to the diagnosis and therapy of SCC.

Keywords

cervical cancer / cellular microRNAs / epigenetics / HPV-associated tumors

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Funding

Российский научный фондRussian Scientific Foundation(23-15-00433)

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