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Novel miRNAs as Potential Regulators of PD-1/PD-L1 Immune Checkpoint, and Prognostic Value of MIR9-1 and MIR124-2 Methylation in Ovarian Cancer

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Abstract

Ovarian cancer (OC) is mostly detected at late stages weighed down with metastasis, and the five-year survival rate of patients is only 30%, which dictates the necessity to develop gentler and more selectively targeted drugs that current chemotherapeutic agents. The search for factors that can influence on the activity of the PD-1/PD-L1 immune checkpoint signaling pathway in tumors is relevant, and microRNAs (miRNAs) play an important role in it. Over the past 5 years, only a few miRNAs (miR-34a, miR-145, and miR-424), which have a regulatory effect on the PD-1/PD-L1 system in OC patients, have been discovered. In present work, the methylation levels of 13 miRNA genes in 26 primary tumors and 19 peritoneal metastases of OC patients were determined and compared with the level of the soluble form of PD-L1 (sPD-L1) in the blood plasma of the same patients. It was shown that the methylation levels of five miRNA genes (MIR124-2, MIR34B/C, MIR9-1, MIR9-3, and MIR339) in tumors are in direct correlation with the sPD-L1 level in the blood plasma. In addition, when analyzing these five genes, a significant association of the methylation level of the MIR9-1 gene with a decrease in the three-year relapse-free survival, and a trend for decrease in the three-year survival rate with the methylation level of the MIR124-2 gene of OC patients were determined. Thus, the first data suggesting the role of inhibitors of the sPD-L1 immune checkpoint for five miRNAs (miR-124, miR-34b, miR-34c, miR-9, miR-339) and the possibility of using hypermethylated MIR9-1 and, presumably, MIR124-2 genes as independent prognostic markers of poor disease-free survival in OC patients were obtained.

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Funding

This work was financially supported by the Russian Science Foundation (project no. 20-15-00368); the analysis of the sPD-L1 level in the blood plasma of patients was performed within the State Task of the Ministry of Education and Science of the Russian Federation for 2020.

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Authors and Affiliations

  1. Blokhin Russian Cancer Research Center, Ministry of Healthcare of the Russian Federation, 115478, Moscow, Russia

    N. E. Kushlinskii, E. A. Korotkova & E. S. Gershtein

  2. Institute of General Pathology and Pathophysiology, 125315, Moscow, Russia

    V. I. Loginov, E. A. Filippova, A. M. Burdennyy, I. V. Pronina, S. S. Lukina & E. A. Braga

  3. Research Centre for Medical Genetics, 115478, Moscow, Russia

    V. I. Loginov & E. A. Braga

  4. Sechenov First Moscow State Medical University, Ministry of Healthcare of the Russian Federation, 119435, Moscow, Russia

    D. O. Utkin & A. V. Smirnova

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  1. N. E. Kushlinskii
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  2. V. I. Loginov
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  3. D. O. Utkin
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  4. E. A. Filippova
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  5. A. M. Burdennyy
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  6. E. A. Korotkova
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  7. I. V. Pronina
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  8. S. S. Lukina
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  9. A. V. Smirnova
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  10. E. S. Gershtein
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  11. E. A. Braga
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Correspondence to E. A. Braga.

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Conflict of interests. The authors declare that they have no conflict of interest.

Statement of compliance with standards of research involving humans as subjects. All procedures performed in the present study were in accordance with the ethical standards of the institutional research ethics committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants involved in the study.

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Translated by D. Novikova

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Kushlinskii, N.E., Loginov, V.I., Utkin, D.O. et al. Novel miRNAs as Potential Regulators of PD-1/PD-L1 Immune Checkpoint, and Prognostic Value of MIR9-1 and MIR124-2 Methylation in Ovarian Cancer. Mol Biol 54, 870–875 (2020). https://doi.org/10.1134/S0026893320060072

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  • DOI: https://doi.org/10.1134/S0026893320060072

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