Russian Journal of GeneticsRussian Journal of GeneticsГенетика0016-67583034-5103The Russian Academy of Sciences70041710.7868/S3034510325120097ГЕНЕТИКА ЧЕЛОВЕКАResearch ArticleThe Role of miR-34a in Predicting the Efficacy of Immunotherapy in Clear Cell Renal Cell CarcinomaРОЛЬ микроРНК-34а В ПРЕДСКАЗАНИИ ЭФФЕКТИВНОСТИ ИММУНОТЕРАПИИ ПРИ СВЕТЛОКЛЕТОЧНОЙ ПОЧЕЧНО-КЛЕТОЧНОЙ КАРЦИНОМЕAsadullinaD. DАсадуллинаД. Дdilara.asadullina@yandex.ruIzmailovA. AИзмайловА. А-PopovaE. VПоповаЕ. В-IvanovaE. AИвановаЕ. А-IzmaylovaS. MИзмайловаС. М-PavlovV. NПавловВ. Н-KhusnutdinovaE. KХуснутдиноваЭ. К-GilyazovaI. RГилязоваИ. Рgilyasova_irina@mail.ruInstitute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of SciencesИнститут биохимии и генетики — обособленное структурное подразделение Уфимского федерального исследовательского центра Российской академии наукBashkir State Medical UniversityБашкирский государственный медицинский университетRepublican Clinical Oncologic DispensaryРеспубликанский клинический онкологический диспансерUfa University of Science and TechnologyУфимский университет науки и технологий151220256112VOL 61, NO12 (2025)ТОМ 61, №12 (2025)909908012026Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://rjraap.com/0016-6758/article/view/700417

Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with a poor prognosis. Despite the successful use of immune checkpoint inhibitors (ICIs) in the treatment of cancer, the lack of reliable predictors of response and toxicity leads to premature discontinuation of therapy in some patients due to disease progression or development of adverse events. The study of exosomal microRNAs revealed that miR-34a may serve as a marker of response to therapy: its level increased in patients with positive response to ICI (0.47 ± 0.16 vs. 0.08 ± 0.16 before treatment, p = 0.02), while no changes were observed in non-responders. miR-200 family showed no significant differences. Although the data require confirmation in a larger sample, miR-34a is promising for the development of a prognostic panel of markers in immunotherapy for ccRCC.

Светлоклеточная почечно-клеточная карцинома (скПКК) — агрессивная опухоль с неблагоприятным прогнозом. Несмотря на успешное применение ингибиторов иммунных контрольных точек (ИКТИ) в лечении онкологических заболеваний, отсутствие надежных предикторов ответа и токсичности приводит к преждевременному прекращению терапии у части пациентов вследствие прогрессирования заболевания или развития нежелательных явлений. Исследование экзосомальных микроРНК выявило, что miR-34a может служить маркером ответа на терапию: ее уровень повышался у пациентов с положительным ответом на ИКТИ (0.47 ± 0.16 против 0.08 ± 0.16 до лечения, p = 0.02), тогда как у неответивших изменений не наблюдалось. Семейство miR-200 не показало значимых различий. Хотя данные требуют подтверждения на большей выборке, miR-34a перспективна для создания прогностической панели маркеров при иммунотерапии скПКК.

immune checkpoint inhibitorsresistanceexosomal microRNAsprognostic markersrenal cell carcinomaингибиторы контрольных точек иммунитетарезистентностьэкзосомальные микроРНКпрогностические маркерыпочечно-клеточная карциномаРабота выполнена за счет средств Программы стратегического академического лидерства Университета (ПРИОРИТЕТ-2030).Chen C., Liu T.S., Zhao S.C. et al. XIAP impairs mitochondrial function during apoptosis by regulating the Bcl-2 family in renal cell carcinoma // Experim. and Therap. Medicine. 2018. V. 15. № 5. P. 4587–4593. https://doi.org/10.3892/etm.2018.5974Cortez M.A., Ivan C., Valdecanas D. et al. PDL1 Regulation by p53 via miR-34 // J. Nat. Cancer Institute. 2016. V. 108. № 1. https://doi.org/10.1093/jnci/djv303Chen L., Gibbons D.L., Goswami S. et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression // Nature Communications. 2014. V. 5. № 1. P. 5241. https://doi.org/10.1038/ncomms6241Ivanova E., Asadullina D., Gilyazova G. et al. Exosomal microRNA levels associated with immune checkpoint inhibitor therapy in clear cell renal cell carcinoma // Biomedicines. 2023. V. 11. № 3. https://doi.org/10.3390/biomedicines11030801Cui M., Wang H., Yao X. et al . Circulating micro-RNAs in cancer: Potential and challenge // Front. in Genetics. 2019. V. 10. https://doi.org/10.3389/fgene.2019.00626Zabeti Touchaei A., Vahidi S. MicroRNAs as regulators of immune checkpoints in cancer immunotherapy: Targeting PD-1/PD-L1 and CTLA-4 pathways // Cancer Cell Int. 2024. V. 24. № 1. P. 102. https://doi.org/10.1186/s12935-024-03293-6Shadbad M.A., Asadzadeh Z., Derakhshani A. et al. A scoping review on the potentiality of PD-L1-inhibiting microRNAs in treating colorectal cancer: Toward single-cell sequencing-guided biocompatible-based delivery // Biomedicine & Pharmacotherapy. 2021. V. 143. https://doi.org/10.1016/j.biopha.2021.112213Yadav R., Khatkar R., Yap K.C.-H. et al. The miRNA and PD-1/PD-L1 signaling axis: An arsenal of immunotherapeutic targets against lung cancer // Cell Death Discovery. 2024. V. 10. № 1. P. 414. https://doi.org/10.1038/s41420-024-02182-1Kim J. Identification of microRNAs as diagnostic biomarkers for breast cancer based on the Cancer Genome Atlas // Diagnostics. 2021. V. 11. № 1. https://doi.org/10.3390/diagnostics11010107Zhang H., Li M., Kaboli P.J. et al. Identification of cluster of differentiation molecule-associated microRNAs as potential therapeutic targets for gastrointestinal cancer immunotherapy // Int. J. Biol. Markers. 2021. V. 36. № 2. P. 22–32. https://doi.org/10.1177/17246008211005473Wei S., Wang K., Huang X. et al. LncRNA MALAT1 contributes to non-small cell lung cancer progression via modulating miR-200a-3p/programmed death-ligand 1 axis // Int. J. Immunopathol. and Pharmacol. 2019. V. 33. https://doi.org/10.1177/2058738419859699Okada N., Lin C.-P., Ribeiro M.C. et al. A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression // Genes & Development. 2014. V. 28. № 5. P. 438–450. https://doi.org/10.1101/gad.233585.113Li W. (Jess), Wang Y., Liu R. et al. MicroRNA-34a: Potent tumor suppressor, cancer stem cell Inhibitor, and potential anticancer therapeutic // Front. in Cell and Developmental Biology. 2021. V. 9. https://doi.org/10.3389/fcell.2021.640587Smolle M.A., Calin H.N., Pichler M. et al. Noncoding RNA s and immune checkpoints – clinical implications as cancer therapeutics // The FEBS J. 2017. V. 284. № 13. P. 1952–1966. https://doi.org/10.1111/febs.14030Basak S.K., Veena M.S., Oh S. et al. The CD44high tumorigenic subsets in lung cancer biospecimens are enriched for low miR-34a expression // PLoS One. 2013. V. 8. № 9. https://doi.org/10.1371/journal.pone.0073195Yadav R., Khatkar R., Yap K.C.-H. et al. The miRNA and PD-1/PD-L1 signaling axis: An arsenal of immunotherapeutic targets against lung cancer // Cell Death Discovery. 2024. V. 10. № 1. P. 414. https://doi.org/10.1038/s41420-024-02182-1Ghandadi M., Sahebkar A. MicroRNA-34a and its target genes: Key factors in cancer multidrug resistance // Current Pharmaceutical Design. 2016. V. 22. № 7. P. 933–939. https://doi.org/10.2174/1381612822666151209153729Monastirioti A., Papadaki C., Kalapanida D. et al. Plasma-based microRNA expression analysis in advanced stage NSCLC patients treated with nivolumab // Cancers. 2022. V. 14. № 19. https://doi.org/10.3390/cancers14194739Li H., Yu G., Shi R. et al. Cisplatin-induced epigenetic activation of miR-34a sensitizes bladder cancer cells to chemotherapy // Mol. Cancer. 2014. V. 13. № 1. https://doi.org/10.1186/1476-4598-13-8Vinall R.L., Ripoll A.Z., Wang S. et al. W. MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53– Rb pathway status // Int. J. Cancer. 2012. V. 130. № 11. P. 2526–2538. https://doi.org/10.1002/ijc.26256Li L., Yuan L., Luo J. et al. MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1 // Clin. and Experim. Medicine. 2013. V. 13. № 2. P. 109–117. https://doi.org/10.1007/s10238-012-0186-5Li X., Ji M., Zhong S. et al. MicroRNA-34a Modulates chemosensitivity of breast cancer cells to adriamycin by targeting Notch1 // Arch. Med. Res. 2012. V. 43. № 7. P. 514–521. https://doi.org/10.1016/j.arcmed.2012.09.007Park E.Y., Chang E., Lee E.J. et al. Targeting of miR34a–NOTCH1 axis reduced breast cancer stemness and chemoresistance // Cancer Research. 2014. V. 74. № 24. P. 7573–7582. https://doi.org/10.1158/0008-5472.CAN-14-1140Cao W., Yang W., Fan R. et al. miR-34a regulates cisplatin-induce gastric cancer cell death by modulating PI3K/AKT/survivin pathway // Tumor Biology. 2014. V. 35. № 2. P. 1287–1295. https://doi.org/10.1007/s13277-013-1171-7Weeraratne S.D., Amani V., Neiss A. et al. miR-34a confers chemosensitivity through modulation of MAGE-A and p53 in medulloblastoma // Neuro-Oncology. 2011. V. 13. № 2. P. 165–175. https://doi.org/10.1093/neuonc/noq179Mortensen M.M., Høyer S., Ørntoft T.F. et al. High miR-449b expression in prostate cancer is associated with biochemical recurrence after radical prostatectomy // BMC Cancer. 2014. V. 14. № 1. https://doi.org/10.1186/1471-2407-14-859Zhou J.-Y., Chen X., Zhao J. et al. MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET // Cancer Letters. 2014. V. 351. № 2. P. 265–271. https://doi.org/10.1016/j.canlet.2014.06.010Yang F., Li Q., Gong Z. et al. MicroRNA-34a targets Bcl-2 and sensitizes human hepatocellular carcinoma cells to sorafenib treatment // Technol. in Cancer Res. & Treatment. 2014. V. 13. № 1. P. 77–86. https://doi.org/10.7785/tcrt.2012.500364Corcoran C., Rani S., O’Driscoll L. MiR-34a is an intracellular and exosomal predictive biomarker for response to docetaxel with clinical relevance to prostate cancer progression // The Prostate. 2014. V. 74. № 13. P. 1320–1334. https://doi.org/10.1002/pros.22848Kojima K., Fujita Y., Nozawa Y. et al. MiR-34a attenuates paclitaxel–esistance of hormone–refractory prostate cancer PC3 cells through direct and indirect mechanisms // The Prostate. 2010. V. 70. № 14. P. 1501–1512. https://doi.org/10.1002/pros.21185Ji Q., Hao X., Zhang M. et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells // PLoS One. 2009. V. 4. № 8. https://doi.org/10.1371/journal.pone.0006816Naor D., Nedvetzki S., Golan I. et al. CD44 in cancer // Critical Rev. in Clin. Labor. Sci. 2002. V. 39. № 6. P. 527–579. https://doi.org/10.1080/10408360290795574Deng C.-X. SIRT1, is it a tumor promoter or tumor suppressor? // Int. J. Biol. Sci. 2009. V. 5. № 2. P. 147–152. https://doi.org/10.7150/ijbs.5.147Kim H.-B., Lee S.-H., Um J.-H. et al. Sensitization of chemo-resistant human chronic myeloid leukemia stem-like cells to Hsp90 inhibitor by SIRT1 inhibition // Int. J. Biol. Sci. 2015. V. 11. № 8. P. 923–934. https://doi.org/10.7150/ijbs.10896Akao Y., Noguchi S., Iio A. et al. Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells // Cancer Letters. 2011. V. 300. № 2. P. 197–204. https://doi.org/10.1016/j.canlet.2010.10.006Fujita Y., Kojima K., Hamada N. et al. Effects of miR-34a on cell growth and chemoresistance in prostate cancer PC3 cells // Biochem. and Biophys. Res. Communications. 2008. V. 377. № 1. P. 114–119. https://doi.org/10.1016/j.bbrc.2008.09.086Wang X., Dong K., Gao P. et al. MicroRNA-34a sensitizes lung cancer cell lines to DDP treatment independent of p53 status // Cancer Biotherapy and Radiopharmaceuticals. 2013. V. 28. № 1. P. 45–50. https://doi.org/10.1089/cbr.2012.1218Lai M., Du G., Shi R. et al. MiR-34a inhibits migration and invasion by regulating the SIRT1/p53 pathway in human SW480 cells // Mol. Med. Reports. 2015. V. 11. № 5. P. 3301–3307. https://doi.org/10.3892/mmr.2015.3182Fan Y.N., Meley D., Pizer B. et al. Mir-34a mimics are potential therapeutic agents for p53-mutated and chemo-resistant brain tumour cells // PLoS One. 2014. V. 9. № 9. https://doi.org/10.1371/journal.pone.0108514Kiss B., Skuginna V., Fleischmann A. et al. Bcl-2 predicts response to neoadjuvant chemotherapy and is overexpressed in lymph node metastases of urothelial cancer of the bladder // Urologic Oncology: Seminars and Original Investigations. 2015. V. 33. № 4. P. 166.e1–166.e8. https://doi.org/10.1016/j.urolonc.2014.12.005Sezgin Alikanoglu A., Yildirim M., Suren D. et al. Expression of cyclooxygenase-2 and Bcl-2 in breast cancer and their relationship with triple-negative disease // J. Official Balkan Union of Oncol. 2014. V. 19. № 2. P. 430–434.Fleischmann A., Huland H., Mirlacher M. et al. Prognostic relevance of Bcl-2 overexpression in surgically treated prostate cancer is not caused by increased copy number or translocation of the gene // The Prostate. 2012. V. 72. № 9. P. 991–997. https://doi.org/10.1002/pros.21504Karnak D., Xu L. Chemosensitization of prostate cancer by modulating Bcl-2 family proteins // Current Drug Targets. 2010. V. 11. № 6. P. 699–707. https://doi.org/10.2174/138945010791170888Bauer C., Hees C., Sterzik A. et al. Proapoptotic and antiapoptotic proteins of the Bcl-2 family regulate sensitivity of pancreatic cancer cells toward gemcitabine and T-cell–mediated cytotoxicity // J. Immunotherapy. 2015. V. 38. № 3. P. 116–126. https://doi.org/10.1097/CJI.0000000000000073Wang H., Zhang Z., Wei X. et al. Small-molecule inhibitor of Bcl-2 (TW-37) suppresses growth and enhances cisplatin-induced apoptosis in ovarian cancer cells // J. Ovarian Res. 2015. V. 8. № 1. P. 3. https://doi.org/10.1186/s13048-015-0130-xLin X., Guan H., Huang Z. et al. Downregulation of Bcl-2 expression by miR-34a mediates palmitate-induced Min6 cells apoptosis // J. Diabetes Res. 2014. V. 2014. P. 1–7. https://doi.org/10.1155/2014/258695Mao S., Sun Q., Xiao H. et al. Secreted miR-34a in astrocytic shedding vesicles enhanced the vulnerability of dopaminergic neurons to neurotoxins by targeting Bcl-2 // Protein & Cell. 2015. V. 6. № 7. P. 529–540. https://doi.org/10.1007/s13238-015-0168-yChen H., Wang J., Hu B. et al. MiR-34a promotes Fas-mediated cartilage endplate chondrocyte apoptosis by targeting Bcl-2 // Mol. and Cell. Biochemistry. 2015. V. 406. № 1–2. P. 21–30. https://doi.org/10.1007/s11010-015-2420-4Chakraborty S., Mazumdar M., Mukherjee S. et al. Restoration of p53/miR–34a regulatory axis decreases survival advantage and ensures Bax–dependent apoptosis of non–small cell lung carcinoma cells // FEBS Letters. 2014. V. 588. № 4. P. 549–559. https://doi.org/10.1016/j.febslet.2013.11.040