THE ALTERATION OF MICRORNA EXPRESSION PROFILES IN CUTANEOUS MALIGNANT MELANOMA AND BENIGN MELANOCYTIC NEVI

DOI: https://doi.org/10.29296/24999490-2021-04-05

S.V. Tsyrenzhapova(1), R.N. Belonogov(1), E.Y. Sergeeva(1, 2), T.G. Ruksha(1) 1-Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University; Partizana Zheleznyaka str., 1, Krasnoyarsk, 660022, Russian Federation; 2-Siberian federal university, Svobodny pr., 79, Krasnoyarsk, 660041, Russian Federation E-mail: [email protected]

Introduction. Early diagnostics of such oncological disease as cutaneous malignant melanoma is strictly important for the decrease of mortality. It is known that microRNA expression in melanoma cells and in bening melanocytic nevi is different, that can be used for improvement of early melanoma diagnostics. The aim of the study. The evaluation of microRNA expression profiles in melanoma and bening melanocytic nevi on the base of microarray; the identification of pathways and target genes for altered microRNA by means of bioinformatics analysis to expanse the view of the melanocytic tumors pathogenesis and to reveal new diagnostic markers. Material and methods. The study included biopsies of patients with melanoma and bening melanocytic nevi. The human melanoma cell line BRO was chosen to investigate the influence of miR-4286 inhibition on target genes expression. The microRNA expression profiles were estimated with a microarray and followed by bioinformatics analysis. MicroRNA target genes expression was assessed by real-time PCR. Results. The 16.15-fold increase of miR-4306 expression level (pFDR=0,036), the 2.11-fold decrease of miR-6853-3p expression level (pFDR=0,036) were revealed in melanoma compared with bening melanocytic nevi. The pathways, proteins, and molecular functions of the detected target genes of the microRNA are associated, mostly, with cell proliferation, motility, and migration. The miR-4286 inhibition in melanoma BRO cells results in the decrease of miR-4286 target genes CCND1 and PLXNA2 expression. Conclusion. The microRNAs expression levels alteration can be supposed to associated with the stages of cell malignant transformation. MicroRNA profiling can be used both the improved comprehension of functional aspects of cancer development and the malignant tumor diagnostics.
Keywords: 
melanoma, microRNA, bening melanocytic nevi

Список литературы: 
  1. Aksenenko M., Palkina N., Komina A., Tashireva L., Ruksha T. Differences in microRNA expression between melanoma and healthy adjacent skin. BMC Dermatol. 2019; 19 (1): 1. https://doi.org/10.1186/s12895-018-0081-1
  2. Ge X., Niture S., Lin M., Cagle P., Li P.A., Kumar D. MicroRNA-205-5p inhibits skin cancer cell proliferation and increase drug sensitivity by targeting TNFAIP8. Sci. Rep. 2021; 11 (1): 5660. https://doi.org/10.1038/s41598-021-85097-6
  3. Davis L.E., Shalin S.C., Tackett A.J. Current state of melanoma diagnosis and treatment. Cancer Biol. Ther. 2019; 20 (11): 1366–79. https://doi.org/10.1080/15384047.2019.1640032
  4. Lu T.X., Rothenberg M.E. MicroRNA. J. Allergy Clin. Immunol. 2018; 141 (4): 1202–7. https://doi.org/10.1016/j.jaci.2017.08.034
  5. Li Y., Kowdley K.V. MicroRNAs in common human diseases. Genomics proteomics bioinformatics. 2012; 10 (5): 246–53. https://doi.org/10.1016/j.gpb.2012.07.005
  6. Motti M.L., Minopoli M., Di Carluccio G., Ascierto P.A., Carriero M.V. MicroRNAs as key players in melanoma cell resistance to MAPK and immune checkpoint inhibitors. Int. J. Mol. Sci. 2020; 21 (12): 4544. https://doi.org/10.3390/ijms21124544
  7. Thyagarajan A., Tsai K.Y., Sahu R.P. MicroRNA heterogeneity in melanoma progression. Semin. Cancer Biol. 2019; 59: 208–20. https://doi.org/10.1016/j.semcancer.2019.05.021
  8. Long Y., Tao H., Karachi A., Grippin A.J., Jin L., Chang Y.E., Zhang W., Dyson K.A., Hou A.Y., Na M., Deleyrolle L.P., Sayour E.J., Rahman M., Mitchell D.A., Lin Z., Huang J. Dysregulation of glutamate transport enhances Treg function that promotes VEGF blockade resistance in glioblastoma. Cancer Res. 2020; 80 (3): 499–509. https://doi.org/10.1158/0008-5472.CAN-19-1577
  9. Dupin E., Le Douarin N.M. Development of melanocyte precursors from the vertebrate neural crest. Oncogene. 2003; 22 (20): 3016–23. https://doi.org/10.1038/sj.onc.1206460
  10. Yang X., Du W.W., Li H., Liu F., Khorshidi A., Rutnam Z.J., Yang B.B. Both mature miR-17-5p and passenger strand miR-17-3p target TIMP3 and induce prostate tumor growth and invasion. Nucleic Acids Res. 2013; 41 (21): 9688–704. https://doi.org/10.1093/nar/gkt680
  11. Shan S.W., Fang L., Shatseva T., Rutnam Z.J., Yang X., Du W., Lu W.Y., Xuan J.W., Deng Z., Yang B.B. Mature miR-17-5p and passenger miR-17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7 and vimentin in different signal pathways. J. Cell Sci. 2013; 126 (6): 1517–30. https://doi.org/10.1242/jcs.122895
  12. Chen L., Huang K., Yi K., Huang Y., Tian X., Kang C. Premature microRNA-based therapeutic: a «one-two punch» against cancers. Cancers (Basel). 2020; 12 (12): 3831. https://doi.org/10.3390/cancers12123831
  13. Place R.F., Li L.C., Pookot D., Noonan E.J., Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc. Natl. Acad. Sci. USA. 2008; 105 (5): 1608–13. https://doi.org/10.1073/pnas.0707594105
  14. Serrano-Gomez S.J., Maziveyi M., Alahari S.K. Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol. Cancer. 2016; 15: 18. https://doi.org/10.1186/s12943-016-0502-x
  15. González-Ruiz L., González-Moles M.Á., González-Ruiz I., Ruiz-Ávila I., Ayén Á., Ramos-Garcia P. An update on the implications of cyclin D1 in melanomas. Pigment Cell Melanoma Res. 2020; 33 (6): 788–805. https://doi.org/10.1111/pcmr.12874
  16. Valiulyte I., Steponaitis G., Kardonaite D., Tamasauskas A., Kazlauskas A. A SEMA3 signaling pathway-based multi-biomarker for prediction of glioma patient survival. Int. J. Mol. Sci. 2020; 21 (19): 7396. https://doi.org/10.3390/ijms21197396
  17. Gabrovska P.N., Smith R.A., Tiang T., Weinstein S.R., Haupt L.M., Griffiths L.R. Semaphorin-plexin signalling genes associated with human breast tumourigenesis. Gene. 2011; 489 (2): 63–9. https://doi.org/10.1016/j.gene.2011.08.024
  18. Tian T.V., Tomavo N., Huot L., Flourens A., Bonnelye E., Flajollet S., Hot D., Leroy X., de Launoit Y., Duterque-Coquillaud M. Identification of novel TMPRSS2:ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2. Oncogene. 2014; 33 (17): 2204–14. https://doi.org/10.1038/onc.2013.176
  19. Xiao M., Li J., Li W., Wang Y., Wu F., Xi Y., Zhang L., Ding C., Luo H., Li Y., Peng L., Zhao L., Peng S., Xiao Y., Dong S., Cao J., Yu W. MicroRNAs activate gene transcription epigenetically as an enhancer trigger. RNA Biol. 2017; 14 (10): 1326–34. https://doi.org/10.1080/15476286.2015.1112487
  20. Vasudevan S., Tong Y., Steitz J.A. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007; 318 (5858): 1931–4. https://doi.org/10.1126/science.1149460