Exosomal MiRNA-146a is Downregulated in Clear Cell Renal Cell Carcinoma Patients with Severe Immune-related Adverse Events

Overview

Journal Noncoding RNA Res

Date 2022 Jul 18

PMID 35846077

Authors

E Ivanova

D Asadullina

R Rakhimov

A Izmailov

Al Izmailov

G Gilyazova

Sh Galimov

V Pavlov

E Khusnutdinova

I Gilyazova

Affiliations

Soon will be listed here.

Abstract

Here we report the results of the pilot project of exosomal miRNA expression levels in clear cell renal cell carcinoma (ccRCC) patients with different clinical response to ICIs (nivolumab) and treatment related toxicity. Immune-related adverse events (irAEs) are a major cause of immune checkpoint inhibitors cancellation and therapy failure. Modern studies demonstrate evidence that exosomes are of great importance in the formation of tumor resistance to ICIs drugs and therapy. We performed exosomal miRNA-146a expression analysis using qPCR on 86 ccRCC patients and revealed a statistically significant (p = 0.01) decreased expression level in ccRCC patients with CTCAE grade 3-4 (M±SEM 1.71 ± 0.13) compared to CTCAE grade 0-2 group (M±SEM 2.30 ± 0.24). The expression levels of miRNA-126, miRNA-218 and miRNA-410 did not show statistically significant differences in the comparison groups (p > 0.05). Association analysis of rs2910164 in the miRNA-146a gene demonstrated that genotype and allele carriers had higher risk of developing severe irAEs (p = 0.03, OR = 6.12; p = 0.01, OR = 2.42, respectively) compare with and carriers. That is the first attempt to identify biomarkers of ICIs treatment efficacy for ccRCC in the Volga-Ural region based on exosomal miRNAs analysis.

Citing Articles

Research progress of extracellular vesicles in the pathogenesis of type IIIA chronic prostatitis.

Cheng L, Luo P, Li W, Chen Q, Gan L, Zhang F Front Immunol. 2025; 16:1496055.

PMID: 40034709 PMC: 11873842. DOI: 10.3389/fimmu.2025.1496055.

Exosomal long non-coding RNAs in cancer: Interplay, modulation, and therapeutic avenues.

Marima R, Basera A, Miya T, Damane B, Kandhavelu J, Mirza S Noncoding RNA Res. 2024; 9(3):887-900.

PMID: 38616862 PMC: 11015109. DOI: 10.1016/j.ncrna.2024.03.014.

Non-Invasive Predictive Biomarkers for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors.

Ponvilawan B, Khan A, Subramanian J, Bansal D Cancers (Basel). 2024; 16(6).

PMID: 38539558 PMC: 10968874. DOI: 10.3390/cancers16061225.

Garcia-Gimenez J, Saadi W, Ortega A, Lahoz A, Suay G, Carretero J Int J Mol Sci. 2024; 25(3).

PMID: 38339019 PMC: 10855819. DOI: 10.3390/ijms25031737.

Biomarkers for immune-related adverse events in cancer patients treated with immune checkpoint inhibitors.

Liang Y, Maeda O, Ando Y Jpn J Clin Oncol. 2024; 54(4):365-375.

PMID: 38183211 PMC: 11771318. DOI: 10.1093/jjco/hyad184.

References

Hao X, Xia L, Qu R, Yang X, Jiang M, Zhou B . Association between miR-146a rs2910164 polymorphism and specific cancer susceptibility: an updated meta-analysis. Fam Cancer. 2017; 17(3):459-468. DOI: 10.1007/s10689-017-0056-0. View

Qiu L, Wang J, Chen M, Chen F, Tu W . Exosomal microRNA‑146a derived from mesenchymal stem cells increases the sensitivity of ovarian cancer cells to docetaxel and taxane via a LAMC2‑mediated PI3K/Akt axis. Int J Mol Med. 2020; 46(2):609-620. PMC: 7307828. DOI: 10.3892/ijmm.2020.4634. View

Wotschofsky Z, Gummlich L, Liep J, Stephan C, Kilic E, Jung K . Integrated microRNA and mRNA Signature Associated with the Transition from the Locally Confined to the Metastasized Clear Cell Renal Cell Carcinoma Exemplified by miR-146-5p. PLoS One. 2016; 11(2):e0148746. PMC: 4747468. DOI: 10.1371/journal.pone.0148746. View

Keewan E, Naser S . MiR-146a polymorphism modulates Notch-1/IL-6 signaling during infection: a possible risk factor for Crohn's disease. Gut Pathog. 2020; 12:48. PMC: 7557229. DOI: 10.1186/s13099-020-00387-0. View

Boguslawska J, Poplawski P, Alseekh S, Koblowska M, Iwanicka-Nowicka R, Rybicka B . MicroRNA-Mediated Metabolic Reprograming in Renal Cancer. Cancers (Basel). 2019; 11(12). PMC: 6966432. DOI: 10.3390/cancers11121825. View

Gilyazova I, Beeraka N, Klimentova E, Bulygin K, Nikolenko V, Izmailov A . Novel MicroRNA Binding Site SNPs and the Risk of Clear Cell Renal Cell Carcinoma (ccRCC): A Case-Control Study. Curr Cancer Drug Targets. 2020; . DOI: 10.2174/1568009620666201120151226. View

Bhaumik D, Scott G, Schokrpur S, Patil C, Campisi J, Benz C . Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 2008; 27(42):5643-7. PMC: 2811234. DOI: 10.1038/onc.2008.171. View

Stevenson M, Banerjee H, Banerjee N, Rawat K, Chen L, Worthington M . A health disparities study of MicroRNA-146a expression in prostate cancer samples derived from African American and European American patients. J Solid Tumors. 2020; 10(2). PMC: 7508462. DOI: 10.5430/jst.v10n2p1. View

Jaiswal R, Luk F, Dalla P, Grau G, Bebawy M . Breast cancer-derived microparticles display tissue selectivity in the transfer of resistance proteins to cells. PLoS One. 2013; 8(4):e61515. PMC: 3625154. DOI: 10.1371/journal.pone.0061515. View

10.

Wei J, Wang J, Zhou Y, Yan S, Li K, Lin H . MicroRNA-146a Contributes to SCI Recovery via Regulating and Expression. Biomed Res Int. 2016; 2016:4013487. PMC: 5086513. DOI: 10.1155/2016/4013487. View

11.

Khorrami S, Zavaran Hosseini A, Mowla S, Soleimani M, Rakhshani N, Malekzadeh R . MicroRNA-146a induces immune suppression and drug-resistant colorectal cancer cells. Tumour Biol. 2017; 39(5):1010428317698365. DOI: 10.1177/1010428317698365. View

12.

Zhang J, Li S, Li L, Li M, Guo C, Yao J . Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 2015; 13(1):17-24. PMC: 4411500. DOI: 10.1016/j.gpb.2015.02.001. View

13.

Chen Y, Chen J, Yin J, Zhou H, He B, Liu Z . Non-Coding RNA Polymorphisms (rs2910164 and rs1333049) Associated With Prognosis of Lung Cancer Under Platinum-Based Chemotherapy. Front Pharmacol. 2021; 12:709528. PMC: 8481925. DOI: 10.3389/fphar.2021.709528. View

14.

Garo L, Ajay A, Fujiwara M, Gabriely G, Raheja R, Kuhn C . MicroRNA-146a limits tumorigenic inflammation in colorectal cancer. Nat Commun. 2021; 12(1):2419. PMC: 8065171. DOI: 10.1038/s41467-021-22641-y. View

15.

Min Q, Wang X, Zhang J, Chen Q, Li S, Liu X . Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365. Exp Cell Res. 2017; 362(2):386-393. DOI: 10.1016/j.yexcr.2017.12.001. View

16.

Semina S, Scherbakov A, Vnukova A, Bagrov D, Evtushenko E, Safronova V . Exosome-Mediated Transfer of Cancer Cell Resistance to Antiestrogen Drugs. Molecules. 2018; 23(4). PMC: 6017149. DOI: 10.3390/molecules23040829. View

17.

Wu C, Li M, Hu C, Duan H . Prognostic role of microRNA polymorphisms in patients with advanced esophageal squamous cell carcinoma receiving platinum-based chemotherapy. Cancer Chemother Pharmacol. 2013; 73(2):335-41. DOI: 10.1007/s00280-013-2364-x. View

18.

Pakzad R, Mohammadian-Hafshejani A, Ghoncheh M, Pakzad I, Salehiniya H . The incidence and mortality of prostate cancer and its relationship with development in Asia. Prostate Int. 2016; 3(4):135-40. PMC: 4685206. DOI: 10.1016/j.prnil.2015.09.001. View

19.

Berraondo P, Sanmamed M, Ochoa M, Etxeberria I, Aznar M, Perez-Gracia J . Cytokines in clinical cancer immunotherapy. Br J Cancer. 2018; 120(1):6-15. PMC: 6325155. DOI: 10.1038/s41416-018-0328-y. View

20.

Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer F, Hesch R . DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001; 61(4):1659-65. View