Features of mitochondrial genes copy numbers and microRNA transcripts in endometrial adenocarcinoma and fibroids patients blood plasma

Introduction. The development of malignant tumors of the uterine body is influenced by many factors, including disturbances in the mitochondrial genome. Abnormalities in the regulation of the mitochondrial genome lead to a decrease in oxidative phosphorylation, as well as inhibition of the mitochondrial apoptosis pathway. To develop effective minimally invasive methods for diagnosing endometrial adenocarcinoma and fibroids, screening of molecular markers in blood plasma is necessary. Such markers may be the gene copy number and the levels of microRNA transcripts. These indicators are sufficiently stable in the extracellular environments of the human body, including blood plasma.
Aim. Тo identify molecular minimally invasive differential markers for endometrial adenocarcinoma and fibroids.
Materials and methods. Laboratory studies of the gene copy number and the levels of microRNA transcripts were carried out using real-time polymerase chain reaction in the blood plasma of 26 patients with endometrial adenocarcinoma, 14 fibroids patients and 20 conditionally healthy women.
Results. Statistically significant differences (p <0.05) were found in the copy number of the HV2 and MT-ND1 genes, as well as in the levels of microRNA transcripts hsa-miR-122-5p and hsa-miR-7106-5p in patients with endometrial adenocarcinoma and fibroids, in patients with endometrial adenocarcinoma and conditionally healthy women. In the blood plasma of patients with endometrial adenocarcinoma, the copy number of HV2 and MT-ND6 was lower by 1.5 (p <0.005) and 1.4 (p <0.05) times, respectively, compared to the level in patients with fibroids, and 1.5 times lower than the level in conditionally healthy women. In the blood plasma of patients with endometrial adenocarcinoma, the levels of microRNA transcripts hsa-miR-122-5p (p <0.005) and hsa-miR-7106-5p (p <0.005) was lower by 8.9 and 3.9 times, respectively, relative to the levels in patients with fibroids. In the blood plasma of endometrial adenocarcinoma patients, the levels of hsa-miR-143-5p, hsa-miR-122-5p and hsa-miR-7106-5p microRNA transcripts was 2.1 (p <0.005), 10.8 (p <0.005) and 5.2 (p <0.005) times lower, respectively, than the levels in conditionally healthy women.
Conclusion. The obtained data on differential differences in the copy number of HV2, MT-ND1, the levels of hsa-miR-122-5p and hsa-miR-7106-5p microRNA transcripts in the blood plasma of patients with endometrial adenocarcinoma and myoma have significant potential for improving minimally invasive diagnostics of these diseases.

1. Kutilin D.S., Nikitin I.S., Kit O.I. Features of some transcription factors gene expression in the malignancy tissues of the corpus uteri. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2019;6(1):57–62. (In Russ.). DOI: 10.17650/2313-805X-2019-6-1-57-62

2. World Cancer Report 2014. World Health Organization. Chapter 5.12. Causes, risk factors, and prevention TOPICS - Do we know what causes endometrial cancer? American Cancer Society. Retrieved 5 January 2015.

3. Kutilin D.S., Gusareva M.A., Kosheleva N.G. The level of replication of genetic loci and minimally invasive assessment of the effectiveness of radiation therapy in patients with rectal cancer. Rossiyskiy bioterapevticheskiy zhurnal = Russian Journal of Biotherapy 2022;21(4):41–9. (In Russ.). DOI: 10.17650/1726-9784-2022-21-4-41-49

4. Tsandekova M.R., Porkhanova N.V., Kit O.I., Kutilin D.S. Minimally invasive molecular diagnostics of high and low grade ovarian serous adenocarcinoma. Onkoginekologiya = Oncogynecology 2021;4(40):35–49. (In Russ.). DOI: 10.52313/22278710_2021_4_35

5. Kutilin D.S., Gusareva M.A., Kosheleva N.G. et al. Disorders in the regulatory network of competitively interacting RNAs and radioresistance of rectal tumors. Mezhdunarodny zhurnal prikladnyh i fundamental’nyh issledovaniy = International Journal of Applied and Fundamental Research 2021;11:12–29. (In Russ.). DOI: 10.17513/mjpfi.13306

6. Kutilin D.S., Ayrapetova T.G., Anistratov P.A. et al. Changes in gene copy in tumor cells and extracellular DNA in patients with lung adenocarcinoma. Byulleten’ eksperimental’noy biologii i meditsiny = Bulletin of Experimental Biology and Medicine 2019;167(6):731–8. (In Russ.). DOI: 10.23683/0321-3005-2017-3-2-74-82

7. Kit O.I., Vodolazhsky D.I., Kutilin D.S. et al. The copyicity of the GSTP1, NFKB1, and HV2 mitochondrial DNA genes in some histological types of gastric cancer. Uspekhi sovremennogo estestvoznaniya = Successes of Modern Natural Science 2015;1–6: 918–21. (In Russ.).

8. Fernfndes J., Michel V., Camoalinga-Ponce V. et al. Circulating mitochondrial DNA level, a noninvasive biomarker for the early detection of gastric cancer. Cancer Epidemiol Biomarkers Prev 2014;23(11):2430–8. DOI: 10.1158/1055-9965.EPI-14-0471

9. Kutilin D.S., Ayrapetova T.G., Anistratov P.A. et al. Changes in the relative copy number of genetic loci in extracellular DNA in patients with lung adenocarcinoma. Izvestiya vuzov. SeveroKavkazskiy region. Estestvennye nauki = Izvestiya Universities. The North Caucasus Region. Natural Sciences 2017;3:74–83. (In Russ.). DOI: 10.23683/0321-3005-2017-3-2-74-82

10. Xu Y., Zhou J., Yuan Q. et al. Quantitative detection of circulating MT-ND1 as a potential biomarker for colorectal cancer. Bosn J Basic Med Sci 2021;21(5):577–86. DOI: 10.17305/bjbms.2021.5576

11. Xu Y.C., Su J., Zhou J.J. et al. Roles of MT-ND1 in cancer. Curr Med Sci 2023;43(5):869–78. DOI: 10.1007/s11596-023-2771-0

12. Kit O.I., Vodolazhsky D.I., Kutilin D.S., Gudueva E.N. Copy variation of genetic loci in gastric cancer. Molekulyarnaya biologiya = Molecular Biology 2015;49(4):658–68. (In Russ.). DOI: 10.7868/S0026898415040096

13. Ding J., Li X., Hu H. TarPmiR: a new approach for microRNA target site prediction. Bioinformatics 2016;32(18):2768–75. DOI: 10.1093/bioinformatics/btw318

14. Balcells I., Cirera S., Busk P.K. Specific and sensitive quantitative RT-PCR of miRNAs with DNA primers. BMC Biotechnol 2011;11(1):70. DOI: 10.1186/1472-6750-11-70

15. Scatena R. Mitochondria and cancer: a growing role in apoptosis, cancer cell metabolism and dedifferentiation. Adv Exp Med Biol 2012;942:287–308. DOI: 10.1007/978-94-007-2869-1_13

16. Liao L.M., Baccarelli A., Shu X.O. et al. Mitochondrial DNA copy number and risk of gastric cancer: a report from the Shanghai Women’s Health Study. Cancer Epidemiol Biomarkers Prev 2011;20(9):1944–9. DOI: 10.1158/1055-9965.EPI-11-0379

17. Voet D.J., Voet J.G., Pratt C.W. Fundamentals of Biochemistry. Chapter 18. Mitochondrial ATP synthesis. 4th edn. Hoboken, NJ: Wiley, 213. Pp. 581–620.

18. Flaquer A., Baumbach C., Kriebel J. et al. Mitochondrial genetic variants identified to be associated with BMI in adults. PLoS One. 2014;9(8):e105116. DOI: 10.1371/journal.pone.0105116

19. Faramin Lashkarian M., Hashemipour N., Niaraki N. et al. MicroRNA-122 in human cancers: from mechanistic to clinical perspectives. Cancer Cell Int 2023;23:29. DOI: 10.1186/s12935-023-02868-z

20. Duan Y., Dong Y., Dang R. et al. MiR-122 inhibits epithelial mesenchymal transition by regulating P4HA1 in ovarian cancer cells. Cell Biol Int 2018;42(11):1564–74. DOI: 10.1002/cbin.11052

21. Yang Y., Liu Y., Liu W. et al. MiR-122 inhibits the cervical cancer development by targeting the oncogene RAD21. Biochem Genet 2022;60(1):303–14. DOI: 10.1007/s10528-021-10098-z

22. Xiong H., Chen Z., Chen W. et al. FKBP-related ncRNA-mRNA axis in breast cancer. Genomics 2020;112(6):4595–607. DOI: 10.21203/rs.3.rs-16732/v1