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Regulation of Gene Expression of Cancer/Testis Antigens in Colorectal Cancer Patients

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Abstract

The transcriptional activity of genes encoding cancer/testis antigens (CTA) and its regulation in colorectal cancer (CRC) is not well understood. The expression of CTA coding genes (CT genes) and possible mechanisms for its regulation, including expression and copy number of DNA methyltransferase genes, copy number of CT genes, microRNA expression, and LINE-1 methylation in CRC were analyzed in this study. The relative expression levels and copy number variation of 19 genes, MAGE-A1, -A2, -A3, -A4, -B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NY-ESO1, SSX2, SCP1, PRAME1, DNMT1, DNMT3A, and DNMT3B, were determined using real-time quantitative PCR. Quantitative methylation of LINE-1 CpG sites was evaluated by pyrosequencing, and multiple parallel sequencing was used to determine the level of microRNA expression. It was found that in colon tumor tissue a multidirectional destabilization of the transcriptional activity of DNMT3A and DNMT3B, associated with copy number variation and a change in expression of the CT genes BAGE, SSX2 and PRAME1, is observed. A strong positive correlation was found between copy number and expression of the BAGE, SSX2, and PRAME1 genes. As a result of multiple parallel sequencing, 6 differentially expressed microRNAs (hsa-miR-143-3p, hsa-miR-26a-5p, hsa-miR-25-3p, hsa-miR-92a-3p, hsa-miR-21-5p, and hsa-let-7i-5p), targeting the CT genes GAGE1, SSX2, PRAME, SCP1, and the gene for DNA methyltransferase 3A (DNMT3A), were found. Data on the mechanisms of the transcriptional activity regulation of CT genes in malignant colon tumors are important for the development of CTA-dependent immunotherapeutic approaches for the treatment of this type of tumor.

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Funding

This work was financially supported by the Ministry of Health of the Russian Federation within the State Task “A study of aberrant regulation of the transcriptional activity of a gene pattern in the development of the malignant transformation of tissues of various nosologies” (project no. AAAA-A18-118072790013-1).

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  1. National Medical Research Centre for Oncology, 344037, Rostov-on-Don, Russia

    D. S. Kutilin

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Correspondence to D. S. Kutilin.

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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.

Additional information

Translated by D. Novikova

Abbreviations: CRC, colorectal cancer; CNV, copy number variation; CTA, cancer/testis antigens; FC, fold change.

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Kutilin, D.S. Regulation of Gene Expression of Cancer/Testis Antigens in Colorectal Cancer Patients. Mol Biol 54, 520–534 (2020). https://doi.org/10.1134/S0026893320040093

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