Cancer therapy failure is a fundamental challenge in cancer treatment. One of the most common reasons for therapy failure is the development of acquired resistance of cancer cells. DNA-damaging agents are frequently used in first-line chemotherapy regimens and DNA damage response, and DNA repair pathways are significantly involved in the mechanisms of chemoresistance. MRE11, a part of the MRN complex involved in double-strand break (DSB) repair, is connected to colorectal cancer (CRC) patients' prognosis. Our previous results showed that single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3'UTR) microRNA (miRNA) binding sites of MRE11 gene are associated with decreased cancer risk but with shorter survival of CRC patients, which implies the role of miRNA regulation in CRC. The therapy of colorectal cancer utilizes oxaliplatin (oxalato(trans-l-1,2-diaminocyclohexane)platinum), which is often compromised by chemoresistance development. There is, therefore, a crucial clinical need to understand the cellular processes associated with drug resistance and improve treatment responses by applying efficient combination therapies. The main aim of this study was to investigate the effect of miRNAs on the oxaliplatin therapy response of CRC patients. By the in silico analysis, miR-140 was predicted to target MRE11 and modulate CRC prognosis. The lower expression of miR-140 was associated with the metastatic phenotype (p < 0.05) and poor progression-free survival (odds ratio (OR) = 0.4, p < 0.05). In the in vitro analysis, we used miRNA mimics to increase the level of miR-140 in the CRC cell line. This resulted in decreased proliferation of CRC cells (p < 0.05). Increased levels of miR-140 also led to increased sensitivity of cancer cells to oxaliplatin (p < 0.05) and to the accumulation of DNA damage. Our results, both in vitro and in vivo, suggest that miR-140 may act as a tumor suppressor and plays an important role in DSB DNA repair and, consequently, CRC therapy response.

1st Faculty of Medicine Charles University Prague Czechia

3rd Faculty of Medicine Charles University Prague Czechia

Biomedical Center in Pilsen Charles University Pilsen Czechia

Department of Molecular Biology of Cancer Institute of Experimental Medicine Czech Academy of Sciences Prague Czechia

Department of Surgery Medical Faculty in Pilsen Charles University Pilsen Czechia

Department of Surgery University Hospital Kralovske Vinohrady and 3rd Faculty of Medicine Charles University Prague Czechia

Eastern Mediterranean University Dr Fazıl Küçük Faculty of Medicine North Cyprus Turkey

Gazimağusa State Hospital Molecular Genetics Research Laboratory North Cyprus Turkey

Institute of Biotechnology Czech Academy of Sciences Vestec Czechia

Surgical Department 1 st Medical Faculty Charles University and Thomayer Hospital Prague Czechia

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Dahlmann M, Werner R, Kortum B, Kobelt D, Walther W, Stein U. Restoring treatment response in colorectal cancer cells by targeting MACC1-dependent ABCB1 expression in combination therapy. Front Oncol (2020) 10:599. doi: 10.3389/fonc.2020.00599 PubMed DOI PMC

Li LY, Guan YD, Chen XS, Yang JM, Cheng Y. DNA Repair pathways in cancer therapy and resistance. Front Pharmacol (2020) 11:629266. doi: 10.3389/fphar.2020.629266 PubMed DOI PMC

Vodenkova S, Jiraskova K, Urbanova M, Kroupa M, Slyskova J, Schneiderova M, et al. . Base excision repair capacity as a determinant of prognosis and therapy response in colon cancer patients. DNA Repair (Amst) (2018) 72:77–85. doi: 10.1016/j.dnarep.2018.09.006 PubMed DOI

Kiwerska K, Szyfter K. DNA Repair in cancer initiation, progression, and therapy-a double-edged sword. J Appl Genet (2019) 60(3-4):329–34. doi: 10.1007/s13353-019-00516-9 PubMed DOI PMC

Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discovery (2005) 4(4):307–20. doi: 10.1038/nrd1691 PubMed DOI

Hashimoto S, Anai H, Hanada K. Mechanisms of interstrand DNA crosslink repair and human disorders. Genes Environ (2016) 38:9. doi: 10.1186/s41021-016-0037-9 PubMed DOI PMC

Situ Y, Chung L, Lee CS, Ho V. MRN (MRE11-RAD50-NBS1) complex in human cancer and prognostic implications in colorectal cancer. Int J Mol Sci (2019) 20(4). doi: 10.3390/ijms20040816 PubMed DOI PMC

Giannini G, Rinaldi C, Ristori E, Ambrosini MI, Cerignoli F, Viel A, et al. . Mutations of an intronic repeat induce impaired MRE11 expression in primary human cancer with microsatellite instability. Oncogene. (2004) 23(15):2640–7. doi: 10.1038/sj.onc.1207409 PubMed DOI

Ihara K, Yamaguchi S, Ueno N, Tani Y, Shida Y, Ogata H, et al. . Expression of DNA double-strand break repair proteins predicts the response and prognosis of colorectal cancer patients undergoing oxaliplatin-based chemotherapy. Oncol Rep (2016) 35(3):1349–55. doi: 10.3892/or.2015.4488 PubMed DOI

Naccarati A, Rosa F, Vymetalkova V, Barone E, Jiraskova K, Di Gaetano C, et al. . Double-strand break repair and colorectal cancer: gene variants within 3’ UTRs and microRNAs binding as modulators of cancer risk and clinical outcome. Oncotarget. (2016) 7(17):23156–69. doi: 10.18632/oncotarget.6804 PubMed DOI PMC

O’Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol (Lausanne) (2018) 9:402. doi: 10.3389/fendo.2018.00402 PubMed DOI PMC

Shah V, Shah J. Recent trends in targeting miRNAs for cancer therapy. J Pharm Pharmacol (2020) 72(12):1732–49. doi: 10.1111/jphp.13351 PubMed DOI

Forterre A, Komuro H, Aminova S, Harada M. A comprehensive review of cancer MicroRNA therapeutic delivery strategies. Cancers (Basel) (2020) 12(7). doi: 10.3390/cancers12071852 PubMed DOI PMC

Ahadi A. The significance of microRNA deregulation in colorectal cancer development and the clinical uses as a diagnostic and prognostic biomarker and therapeutic agent. Noncoding RNA Res (2020) 5(3):125–34. doi: 10.1016/j.ncrna.2020.08.003 PubMed DOI PMC

McGeary SE, Lin KS, Shi CY, Pham TM, Bisaria N, Kelley GM, et al. . The biochemical basis of microRNA targeting efficacy. Science (2019) 366(6472). doi: 10.1126/science.aav1741 PubMed DOI PMC

Ru Y, Kechris KJ, Tabakoff B, Hoffman P, Radcliffe RA, Bowler R, et al. . The multiMiR r package and database: integration of microRNA-target interactions along with their disease and drug associations. Nucleic Acids Res (2014) 42(17):e133. doi: 10.1093/nar/gku631 PubMed DOI PMC

Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, et al. . TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res (2016) 44(8):e71. doi: 10.1093/nar/gkv1507 PubMed DOI PMC

Lamarche BJ, Orazio NI, Weitzman MD. The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett (2010) 584(17):3682–95. doi: 10.1016/j.febslet.2010.07.029 PubMed DOI PMC

Mah LJ, El-Osta A, Karagiannis TC. gammaH2AX: a sensitive molecular marker of DNA damage and repair. Leukemia. (2010) 24(4):679–86. doi: 10.1038/leu.2010.6 PubMed DOI

Gherman A, Balacescu L, Gheorghe-Cetean S, Vlad C, Balacescu O, Irimie A, et al. . Current and new predictors for treatment response in metastatic colorectal cancer. the role of circulating miRNAs as biomarkers. Int J Mol Sci (2020) 21(6). doi: 10.3390/ijms21062089 PubMed DOI PMC

Zheng M, Liu J, Meng C, Tang K, Liao J. Prognostic and clinicopathological importance of microRNA-140 expression in cancer patients: a meta-analysis. World J Surg Oncol (2021) 19(1):266. doi: 10.1186/s12957-021-02380-6 PubMed DOI PMC

Fang Z, Yin S, Sun R, Zhang S, Fu M, Wu Y, et al. . miR-140-5p suppresses the proliferation, migration and invasion of gastric cancer by regulating YES1. Mol Cancer (2017) 16(1):139. doi: 10.1186/s12943-017-0708-6 PubMed DOI PMC

Yuan Y, Shen Y, Xue L, Fan H. miR-140 suppresses tumor growth and metastasis of non-small cell lung cancer by targeting insulin-like growth factor 1 receptor. PloS One (2013) 8(9):e73604. doi: 10.1371/journal.pone.0073604 PubMed DOI PMC

Meng Y, Gao R, Ma J, Zhao J, Xu E, Wang C, et al. . MicroRNA-140-5p regulates osteosarcoma chemoresistance by targeting HMGN5 and autophagy. Sci Rep (2017) 7(1):416. doi: 10.1038/s41598-017-00405-3 PubMed DOI PMC

Lu X, Liu R, Wang M, Kumar AK, Pan F, He L, et al. . MicroRNA-140 impedes DNA repair by targeting FEN1 and enhances chemotherapeutic response in breast cancer. Oncogene. (2020) 39(1):234–47. doi: 10.1038/s41388-019-0986-0 PubMed DOI

Liu D, Chen C, Cui M, Zhang H. miR-140-3p inhibits colorectal cancer progression and its liver metastasis by targeting BCL9 and BCL2. Cancer Med (2021) 10(10):3358–72. doi: 10.1002/cam4.3840 PubMed DOI PMC

Shahabi A, Naghili B, Ansarin K, Montazeri V, Zarghami N. miR-140 and miR-196a as potential biomarkers in breast cancer patients. Asian Pac J Cancer Prev (2020) 21(7):1913–8. doi: 10.31557/APJCP.2020.21.7.1913 PubMed DOI PMC

Wang W, Wang M, Xu J, Long F, Zhan X. Overexpressed GATA3 enhances the sensitivity of colorectal cancer cells to oxaliplatin through regulating MiR-29b. Cancer Cell Int (2020) 20:339. doi: 10.1186/s12935-020-01424-3 PubMed DOI PMC

Lin Z, Pan J, Chen L, Wang X, Chen Y. MiR-140 resensitizes cisplatin-resistant NSCLC cells to cisplatin treatment through the SIRT1/ROS/JNK pathway. Onco Targets Ther (2020) 13:8149–60. doi: 10.2147/OTT.S261799 PubMed DOI PMC

Altan B, Yokobori T, Ide M, Bai T, Yanoma T, Kimura A, et al. . High expression of MRE11-RAD50-NBS1 is associated with poor prognosis and chemoresistance in gastric cancer. Anticancer Res (2016) 36(10):5237–47. PubMed

Pavelitz T, Renfro L, Foster NR, Caracol A, Welsch P, Lao VV, et al. . MRE11-deficiency associated with improved long-term disease free survival and overall survival in a subset of stage III colon cancer patients in randomized CALGB 89803 trial. PloS One (2014) 9(10):e108483. doi: 10.1371/journal.pone.0108483 PubMed DOI PMC

Cumova A, Vymetalkova V, Opattova A, Bouskova V, Pardini B, Kopeckova K, et al. . Genetic variations in 3’UTRs of SMUG1 and NEIL2 genes modulate breast cancer risk, survival and therapy response. Mutagenesis. (2021) 36(4):269–79. doi: 10.1093/mutage/geab017 PubMed DOI

Bian L, Meng Y, Zhang M, Li D. MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment. Mol Cancer (2019) 18(1):169. doi: 10.1186/s12943-019-1100-5 PubMed DOI PMC

Commentary: Special Issue: Current Understanding of Colorectal and Pancreatic Cancers

Complex molecular profile of DNA repair genes in epithelial ovarian carcinoma patients with different sensitivity to platinum-based therapy