Expression profile of cellular microRNAs and their potential role in cervical cancer
- Authors: Elkin D.S.1, Faskhutdinov R.S.1, Zvereva O.V.1, Fedorova M.D.1, Katargin A.N.1, Pavlova L.S.1, Zhordania K.I.1, Mustafina E.A.1, Vinokurova S.V.1
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Affiliations:
- Blokhin National Medical Research Center of Oncology
- Issue: Vol 29, No 3 (2024)
- Pages: 195-210
- Section: Original Study Articles
- Submitted: 16.10.2024
- Accepted: 30.11.2024
- Published: 21.12.2024
- URL: https://rjonco.com/1028-9984/article/view/637142
- DOI: https://doi.org/10.17816/onco637142
- ID: 637142
Cite item
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.
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About the authors
Danila S. Elkin
Blokhin National Medical Research Center of Oncology
Author for correspondence.
Email: d.elkin@ronc.ru
ORCID iD: 0000-0002-4793-6063
SPIN-code: 9946-6863
Russian Federation, Moscow
Radik S. Faskhutdinov
Blokhin National Medical Research Center of Oncology
Email: r.faskhutdinov@ronc.ru
ORCID iD: 0000-0002-0050-7798
Russian Federation, Moscow
Olga V. Zvereva
Blokhin National Medical Research Center of Oncology
Email: zvereva.owl@mail.ru
ORCID iD: 0009-0007-7691-3235
Russian Federation, Moscow
Mariya D. Fedorova
Blokhin National Medical Research Center of Oncology
Email: m.d.fedorova@ronc.ru
ORCID iD: 0000-0002-8813-7516
SPIN-code: 4943-5931
Cand. Sci. (Biology)
Russian Federation, MoscowAleksej N. Katargin
Blokhin National Medical Research Center of Oncology
Email: a.katargin@ronc.ru
ORCID iD: 0000-0002-7405-0671
Cand. Sci. (Biology)
Russian Federation, MoscowLarisa S. Pavlova
Blokhin National Medical Research Center of Oncology
Email: l.pavlova@ronc.ru
ORCID iD: 0000-0003-3993-4823
Russian Federation, Moscow
Kirill I. Zhordania
Blokhin National Medical Research Center of Oncology
Email: k.zhordania@ronc.ru
ORCID iD: 0000-0003-1380-3710
SPIN-code: 6271-8954
MD, Dr. Sci. (Medicine), Professor
Russian Federation, MoscowEkaterina A. Mustafina
Blokhin National Medical Research Center of Oncology
Email: e.mustafina@ronc.ru
ORCID iD: 0000-0002-1009-0383
MD, Cand. Sci. (Medicine)
Russian Federation, MoscowSvetlana V. Vinokurova
Blokhin National Medical Research Center of Oncology
Email: s.vinokurova@ronc.ru
ORCID iD: 0000-0003-1615-3928
SPIN-code: 3453-4502
MD, Cand. Sci. (Medicine)
Russian Federation, MoscowReferences
- Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–263. doi: 10.3322/caac.21834
- Egawa N, Egawa K, Griffin H, et al. Viruses. 2015;7(7):3863–3890. doi: 10.3390/v7072802
- Scarth J, Patterson M, Morgan E, Macdonald A. The human papillomavirus oncoproteins: a review of the host pathways targeted on the road to transformation. J Gen Virol. 2021;102(3): 001540. doi: 10.1099/jgv.0.001540
- Thierry F. Transcriptional regulation of the papillomavirus oncogenes by cellular and viral transcription factors in cervical carcinoma. Virology. 2009;384(2):375–379. doi: 10.1016/j.virol.2008.11.014
- Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol. 2007;212(4):356–367. doi: 10.1002/path.2192
- Vinokurova S, Wentzensen N, Kraus I, et al. Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res. 2008;68(1):307–313. doi: 10.1158/0008-5472.CAN-07-2754
- Arias-Pulido H, Peyton C, Joste N, et al. Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol. 2006;44(5):1755–1762. doi: 10.1128/JCM.44.5.1755-1762.2006
- Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer. 2001;92(2):276–284. doi: 10.1002/ijc.1174
- Sano T, Oyama T, Kashiwabara K, et al. Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol. 1998;153(6):1741–1748. doi: 10.1016/S0002-9440(10)65689-1
- Shang R, Lee S, Senavirathne G, Lai EC. microRNAs in action: biogenesis, function and regulation. Nat Rev Genet. 2023;24(12):816–833. doi: 10.1038/s41576-023-00611-y
- Chauhan P, Pramodh S, Hussain A, et al. Understanding the role of miRNAs in cervical cancer pathogenesis and therapeutic responses. Front Cell Dev Biol. 2024;12:1397945. doi: 10.3389/fcell.2024.1397945
- Robinson M, McCarthy D, Smyth G. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40. doi: 10.1093/bioinformatics/btp616
- Goedhart J, Luijsterburg MS. VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots. Sci Rep. 2020;10(1):20560. doi: 10.1038/s41598-020-76603-3
- Xu F, Wang Y, Ling Y, et al. dbDEMC 3.0: Functional Exploration of Differentially Expressed miRNAs in Cancers of Human and Model Organisms. Genomics Proteomics Bioinformatics. 2022;20(3):446–454. doi: 10.1016/j.gpb.2022.04.006
- Tang D, Chen M, Huang X, et al. SRplot: A free online platform for data visualization and graphing. PLoS One. 2023;18(11):e0294236. doi: 10.1371/journal.pone.0294236
- Kern F, Aparicio-Puerta E, Li Y, et al. miRTargetLink 2.0-interactive miRNA target gene and target pathway networks. Nucleic Acids Res. 2021;49(W1):W409–W16. doi: 10.1093/nar/gkab297
- Skoufos G, Kakoulidis P, Tastsoglou S, et al. TarBase-v9.0 extends experimentally supported miRNA-gene interactions to cell-types and virally encoded miRNAs. Nucleic Acids Res. 2024;52(D1):D304–D10. doi: 10.1093/nar/gkad1071
- Vasaikar S, Straub P, Wang J, Zhang B. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 2018;46(D1):D956–D63. doi: 10.1093/nar/gkx1090
- Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523. doi: 10.1038/s41467-019-09234-6
- Goldman M, Craft B, Hastie M, et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020;38(6):675–678. doi: 10.1038/s41587-020-0546-8
- Cruz-De la Rosa M, Jimenez-Wences H, Alarcon-Millan J, et al. miR-218-5p/RUNX2 Axis Positively Regulates Proliferation and Is Associated with Poor Prognosis in Cervical Cancer. Int J Mol Sci. 2022;23(13):6993. doi: 10.3390/ijms23136993
- Zhu L, Tu H, Liang Y, Tang D. MiR-218 produces anti-tumor effects on cervical cancer cells in vitro. World J Surg Oncol. 2018;16(1):204. doi: 10.1186/s12957-018-1506-3
- Wang P, Zhai G, Bai Y. Values of miR-34a and miR-218 expression in the diagnosis of cervical cancer and the prediction of prognosis. Oncol Lett. 2018;15(3):3580–3585. doi: 10.3892/ol.2018.7791
- Kogo R, How C, Chaudary N, et al. The microRNA-218~Survivin axis regulates migration, invasion, and lymph node metastasis in cervical cancer. Oncotarget. 2015;6(2):1090–1100. doi: 10.18632/oncotarget.2836
- Yamamoto N, Kinoshita T, Nohata N, et al. Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion by targeting focal adhesion pathways in cervical squamous cell carcinoma. Int J Oncol. 2013;42(5):1523–1532. doi: 10.3892/ijo.2013.1851
- Szekerczes T, Galamb A, Varga N, et al. Increased miR-20b Level in High Grade Cervical Intraepithelial Neoplasia. Pathol Oncol Res. 2020;26(4):2633–2640. doi: 10.1007/s12253-020-00852-w
- Cheng Y, Geng L, Zhao L, et al. Human papillomavirus E6-regulated microRNA-20b promotes invasion in cervical cancer by targeting tissue inhibitor of metalloproteinase 2. Mol Med Rep. 2017;16(4):5464–5470. doi: 10.3892/mmr.2017.7231
- Lajer C, Garnaes E, Friis-Hansen L, et al. The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer. Br J Cancer. 2012;106(9):1526–1534. doi: 10.1038/bjc.2012.109
- Wald A, Hoskins E, Wells S, et al. Alteration of microRNA profiles in squamous cell carcinoma of the head and neck cell lines by human papillomavirus. Head Neck. 2011;33(4):504–512. doi: 10.1002/hed.21475
- Haga R, Ridley A. Rho GTPases: Regulation and roles in cancer cell biology. Small GTPases. 2016;7(4):207–221. doi: 10.1080/21541248.2016.1232583
- Castro-Munoz L, Rocha-Zavaleta L, Lizano M, et al. Alteration of the IFN-Pathway by Human Papillomavirus Proteins: Antiviral Immune Response Evasion Mechanism. Biomedicines. 2022;10(11):2965. doi: 10.3390/biomedicines10112965
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