MicroRNA as a biomarker for primary cutaneous T-cell non-Hodgkin’s lymphoma

I n t r o d u c t i o n . Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal nonHodgkin’s lymphomas with primary skin involvement. The diagnosis of CTCL is often challenging because, in the early stages, malignant lymphoma can have clinical and morphological features that are similar to benign dermatological conditions such as chronic eczematous dermatitis, psoriasis, pityriasis rubra pilaris, or fungal skin infections. Additionally, unlike B-cell non-Hodgkin’s lymphomas, T-cell tumor proliferation often lacks specifi c immunophenotypic markers, characteristic chromosomal aberrations and tends to be polyclonal, which signifi cantly complicates the use of immunohistochemical and molecular genetic methods in diff erential diagnosis. However, both genetic and epigenetic factors, microRNAs (miRNAs) in particular, are involved in the pathogenesis of CTCL.

A i m . To identify a specifi c miRNA profi le of the tumor substrate that can diff erentiate CTCL from benign skin lesions and determine their role in the pathogenetic mechanisms of disease development. Materials and methods. Using real-time reverse transcription polymerase chain reaction levels of expression of miRNAs-126, -145, -125b, -203a, -99, -23a, -146a, and let-7g were analyzed in 10 formalin-fi xed paraffi nembedded skin biopsy samples from patients with CTCL, 10 skin biopsy samples from patients with psoriasis, and 20 skin biopsy samples from patients with eczema.

R e s u l t s . Comparative analysis of miRNA expression levels between CTCL and benign skin samples showed a statistically signifi cant decrease in the miRNA-203a expression and an increase in the miRNA-146a and let-7g expression in tumor samples (p < 0,05). ROC analysis demonstrated that the let-7g level and the composite biomarker, i.e. the ratio of miRNA-203a/miRNA-146a, are the highly sensitive and specifi c markers for CTCL diagnosis.

C o n c l u s i o n . The analysis of miRNA expression levels serve a promising tool for the diff erential diagnosis of dermatotropic T-cell lymphoid hematologic malignancies and non-hematopoietic skin diseases.

1. Yu X., Li Z., Liu J. MiRNAs in primary cutaneous lymphomas. Cell Prolif. 2015;48(3):271-277. DOI: 10.1111/cpr.12179.

2. Ralfkiaer U., Hagedorn P.H., Bangsgaard N. et al. Diagnostic microRNA profi ling in cutaneous T-cell lymphoma (CTCL). Blood. 2011;118(22):5891-5900. DOI: 10.1182/blood-2011-06-358382.

3. Walia R., Yeung C.C.S. An update on molecular biology of cutaneous T cell lymphoma. Front. Oncol. 2020;9:1558. DOI: 10.3389/fonc.2019.01558.

4. Bin Masroni M.S., Ling Eng G.W., Jeon A.J. et al. MicroRNA expression signature as a biomarker in the diagnosis of nodal T-cell lymphomas. Cancer Cell Int. 2024;24(1):48. DOI: 10.1186/s12935-024-03226-3.

5. Shen X., Wang B., Li K. et al. MicroRNA signatures in diagnosis and prognosis of cutaneous T-cell lymphoma. J. Invest. Dermatol. 2018;138(9):2024-2032. DOI: 10.1016/j.jid.2018.03.1500.

6. Crisafulli L., Ficara F. Micro-RNAs: A safety net to protect hematopoietic stem cell self-renewal. Wiley Interdiscip. Rev. RNA. 2022;13(3):e1693. DOI: 10.1002/wrna.1693.

7. Nassiri S.M., Ahmadi Afshar N., Almasi P. Insight into microRNAs’ involvement in hematopoiesis: current standing point of fi ndings. Stem Cell Res. Ther. 2023;14(1):282. DOI: 10.1186/s13287-023-03504-3.

8. Matthews H.K., Bertoli C., de Bruin R.A.M. Cell cycle control in cancer. Nat. Rev. Mol. Cell Biol. 2022;23(1):74-88. DOI: 10.1038/s41580-021-00404-3.

9. Chivukula R.R., Mendell J.T. Circular reasoning: microRNAs and cell-cycle control. Trends Biochem. Sci. 2008;33(10):474-481. DOI: 10.1016/j.tibs.2008.06.008.

10. Tastsoglou S., Skoufos G., Miliotis M. DIANA-miRPath v4.0: expanding target-based miRNA functional analysis in cell-type and tissue contexts. Nucleic Acids Res. 2023;51(W1):W154-W159. DOI: 10.1093/nar/gkad431.

11. Lee H., Han S., Kwon C.S. et al. Biogenesis and regulation of the let-7 miRNAs and their functional implications. Protein Cell. 2016;7(2):100-113. DOI: 10.1007/s13238-015-0212-y.

12. Chirshev E., Oberg K.C., Ioff e Y.J. et al. Let-7 as biomarker, prognostic indicator, and therapy for precision medicine in cancer. Clin. Transl. Med. 2019;8(1):24. DOI: 10.1186/s40169-019-0240-y.

13. Biamonte F., Santamaria G., Sacco A. et al. MicroRNA let-7g acts as tumor suppressor and predictive biomarker for chemoresistance in human epithelial ovarian cancer. Sci. Rep. 2019;9(1):5668. DOI: 10.1038/s41598-019-42221-x.

14. Chang C.M., Wong H.S., Huang C.Y. et al. Functional eff ects of let-7g expression in colon cancer metastasis. Cancers (Basel). 2019;11(4):489. DOI: 10.3390/cancers11040489.

15. Boyerinas B., Park S.M., Hau A. et al. The role of let-7 in cell diff erentiation and cancer. Endocr. Relat. Cancer. 2010;17(1):F19- F36. DOI: 10.1677/ERC-09-0184.

16. Wells A.C., Daniels K.A., Angelou C.C. et al. Modulation of let-7 miRNAs controls the diff erentiation of eff ector CD8 T cells. eLife. 2017;6:e26398. DOI: 10.7554/eLife.26398.

17. Mazan-Mamczarz K., Gartenhaus R.B. Role of microRNA deregulation in the pathogenesis of diff use large B-cell lymphoma (DLBCL). Leuk. Res. 2013;37(11):1420-1428. DOI: 10.1016/j.leukres.2013.08.020.

18. Poliseno L., Haimovic A., Segura M.F. et al. Histologyspecifi c microRNA alterations in melanoma. J. Invest. Dermatol. 2012;132(7):1860-1868. DOI: 10.1038/jid.2011.451.

19. Yang H., Wang L., Tang X. et al. miR-203a suppresses cell proliferation by targeting E2F transcription factor 3 in human gastric cancer. Oncol. Lett. 2017;14(6):7687- 7690. DOI: 10.3892/ol.2017.7199.

20. Chen L., Gao H., Liang J. et al. miR-203a-3p promotes colorectal cancer proliferation and migration by targeting PDE4D. Am. J. Cancer Res. 2018;8(12):2387-2401.

21. Entezari M., Soltani B.M., Sadeghizadeh M. MicroRNA-203a inhibits breast cancer progression through the PI3K/Akt and Wnt pathways. Sci. Rep. 2024;14(1):4715. DOI: 10.1038/s41598-024-52940-5.

22. Wang K., Xu Z., Wang N. et al. MicroRNA and gene networks in human diff use large B-cell lymphoma. Oncol. Lett. 2014;8(5):2225-2232. DOI: 10.3892/ol.2014.2438.

23. He J., Han Z., An Z. et al. The miR-203a regulatory network aff ects the proliferation of chronic myeloid leukemia K562 cells. Front. Cell Dev. Biol. 2021;9:616711. DOI: 10.3389/fcell.2021.616711.

24. Petriv O.I., Kuchenbauer F., Delaney A.D. et al. Comprehensive microRNA expression profi ling of the hematopoietic hierarchy. Proc. Natl. Acad. Sci. U S A. 2010;107(35):15443-15448. DOI: 10.1073/pnas.1009320107.

25. Kookli K., Soleimani K.T., Amr E.F. et al. Role of microRNA-146a in cancer development by regulating apoptosis. Pathol. Res. Pract. 2024;254:155050. DOI: 10.1016/j.prp.2023.155050.

26. Zhao J.L., Starczynowski D.T. Role of microRNA-146a in normal and malignant hematopoietic stem cell function. Front. Genet. 2014;5:219. DOI: 10.3389/fgene.2014.00219.

27. Li Y., Wang X., Yang K. MicroRNA-146a inhibits progression and immune evasion in diff use large B-cell lymphomas by targeting programmed cell death ligand 1. Iran J. Immunol. 2025;22(1):34-46. DOI: 10.22034/iji.2025.104027.2874.

28. Yan F., Meng W., Ye S. et al. MicroRNA 146a as a potential regulator involved in the pathogenesis of atopic dermatitis. Mol. Med. Rep. 2019;20(5):4645- 4653. DOI: 10.3892/mmr.2019.10695.

29. Naddeo M., Broseghini E., Venturi F. et al. Association of miR-146a-5p and miR-21-5p with prognostic features in melanomas. Cancers (Basel). 2024;16(9):1688. DOI: 10.3390/cancers16091688.

30. Di Raimondo C., Han Z., Su C. et al. Identifi cation of a distinct miRNA regulatory network in the tumormicroenvironment of transformed mycosis fungoides. Cancers (Basel). 2021;13(22):5854. DOI: 10.3390/cancers13225854.

31. Papadaki M., Bourdakou M.M., Piperi C. et al. Diagnostic and therapeutic impact of miR-142, miR-146a, and miR-155 on cutaneous T-cell lymphoma. Eur. J. Dermatol. 2025;35(3):174-191. DOI: 10.1684/ejd.2025.4887.

32. Wen P., Xie Y., Wang L. The role of microRNA in pathogenesis, diagnosis, diff erent variants, treatment and prognosis of mycosis fungoides. Front. Oncol. 2021;11:752817. DOI: 10.3389/fonc.2021.752817.

33. Manso R., Martínez-Magunacelaya N., Eraña-Tomás I. et al. Mycosis fungoides progression could be regulated by microRNAs. PLoS One. 2018;13(6):e0198477. DOI: 10.1371/journal.pone.0198477.

34. Bueno M.J., Malumbres M. MicroRNAs and the cell cycle. Biochim. Biophys. Acta. 2011;1812(5):592-601. DOI: 10.1016/j.bbadis.2011.02.002.