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A-to-I edited miR-411-5p targets MET and promotes TKI response in NSCLC-resistant cells

Oncogene volume 42, pages 1597–1606 (2023)Cite this article

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Abstract

Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation have an initial favorable clinical response to the tyrosine kinase inhibitors (TKIs). Unfortunately, rapid resistance occurs mainly because of genetic alterations, including amplification of the hepatocyte growth factor receptor (MET) and its abnormal activity. The RNA post-transcriptional modifications that contribute to aberrant expression of MET in cancer are largely under-investigated and among them is the adenosine-to-inosine (A-to-I) RNA editing of microRNAs. A reduction of A-to-I editing in position 5 of miR-411-5p has been identified in several cancers, including NSCLC. In this study, thanks to cancer-associated gene expression analysis, we assessed the effect of the edited miR-411-5p on NSCLC cell lines. We found that edited miR-411-5p directly targets MET and negatively affects the mitogen-activated protein kinases (MAPKs) pathway. Considering the predominant role of the MAPKs pathway on TKIs resistance, we generated NSCLC EGFR mutated cell lines resistant to TK inhibitors and evaluated the effect of edited miR-411-5p overexpression. We found that the edited miR-411-5p reduces proliferation and induces apoptosis, promoting EGFR TKIs response in NSCLC-resistant cells.

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Fig. 1: Edited miR-411-5p targets MET and impacts the ERK/MAPK and PI3K/AKT pathways.
Fig. 2: Edited miR-411-5p reduces c-Fos expression and AP1 activity.
Fig. 3: Edited miR-411-5p reduces cell proliferation in response to TKIs.
Fig. 4: Edited miR-411-5p induces apoptosis in response to TKIs.

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Data availability

The datasets generated and/or analyzed during the current study have been submitted to the GEO repository (accession # GSE221334).

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    Article  PubMed  Google Scholar 

  2. Lin JJ, Cardarella S, Lydon CA, Dahlberg SE, Jackman DM, Janne PA, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol. 2016;11:556–65.

    Article  PubMed  Google Scholar 

  3. Cheng L, Alexander RE, Maclennan GT, Cummings OW, Montironi R, Lopez-Beltran A, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25:347–69.

    Article  CAS  PubMed  Google Scholar 

  4. Gelatti ACZ, Drilon A, Santini FC. Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Lung Cancer. 2019;137:113–22.

    Article  PubMed  Google Scholar 

  5. Tan CS, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. 2015;16:e447–e59.

    Article  CAS  PubMed  Google Scholar 

  6. Remon J, Moran T, Majem M, Reguart N, Dalmau E, Marquez-Medina D, et al. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: a new era begins. Cancer Treat Rev. 2014;40:93–101.

    Article  CAS  PubMed  Google Scholar 

  7. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725–37.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Coleman N, Hong L, Zhang J, Heymach J, Hong D, Le X. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open. 2021;6:100319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guo R, Luo J, Chang J, Rekhtman N, Arcila M, Drilon A. MET-dependent solid tumours - molecular diagnosis and targeted therapy. Nat Rev Clin Oncol. 2020;17:569–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang J, Babic A. Regulation of the MET oncogene: molecular mechanisms. Carcinogenesis. 2016;37:345–55.

    Article  CAS  PubMed  Google Scholar 

  11. Friedlaender A, Drilon A, Banna GL, Peters S, Addeo A. The METeoric rise of MET in lung cancer. Cancer. 2020;126:4826–37.

    Article  CAS  PubMed  Google Scholar 

  12. Song H, Liu D, Dong S, Zeng L, Wu Z, Zhao P, et al. Epitranscriptomics and epiproteomics in cancer drug resistance: therapeutic implications. Signal Transduct Target Ther. 2020;5:193.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Romano G, Saviana M, Le P, Li H, Micalo L, Nigita G. et al. Non-Coding RNA Editing in Cancer Pathogenesis. Cancers (Basel). 2020;12:1845.

    Article  PubMed  Google Scholar 

  14. Hua H, Zeng J, Xing H, He Y, Han L, Zhang N, et al. The RNA editing enzyme ADAR modulated by the rs1127317 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma. Life Sci. 2022;296:120408.

    Article  CAS  PubMed  Google Scholar 

  15. Han L, Diao L, Yu S, Xu X, Li J, Zhang R, et al. The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers. Cancer Cell. 2015;28:515–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abrahamsson AE, Geron I, Gotlib J, Dao KH, Barroga CF, Newton IG, et al. Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci. 2009;106:3925–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nigita G, Distefano R, Veneziano D, Romano G, Rahman M, Wang K, et al. Tissue and exosomal miRNA editing in Non-Small Cell Lung Cancer. Sci Rep. 2018;8:10222.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019;234:5451–65.

    Article  CAS  PubMed  Google Scholar 

  19. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Acunzo M, Romano G, Wernicke D, Croce CM. MicroRNA and cancer–a brief overview. Adv Biol Regul. 2015;57:1–9.

    Article  CAS  PubMed  Google Scholar 

  21. Acunzo M, Romano G, Palmieri D, Lagana A, Garofalo M, Balatti V, et al. Cross-talk between MET and EGFR in non-small cell lung cancer involves miR-27a and Sprouty2. Proc Natl Acad Sci. 2013;110:8573–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tibaldi C, D’Incecco A, Lagana A. MicroRNAs and Targeted Therapies in Non-small Cell Lung Cancer: Minireview. Anticancer Agents Med Chem. 2015;15:694–700.

    Article  CAS  PubMed  Google Scholar 

  23. Brighenti M. MicroRNA and MET in lung cancer. Ann Transl Med. 2015;3:68.

    PubMed  PubMed Central  Google Scholar 

  24. Acunzo M, Visone R, Romano G, Veronese A, Lovat F, Palmieri D, et al. miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222. Oncogene. 2012;31:634–42.

    Article  CAS  PubMed  Google Scholar 

  25. Gu YF, Zhang H, Su D, Mo ML, Song P, Zhang F, et al. miR-30b and miR-30c expression predicted response to tyrosine kinase inhibitors as first line treatment in non-small cell lung cancer. Chin Med J. 2013;126:4435–9.

    CAS  PubMed  Google Scholar 

  26. Saleh AD, Cheng H, Martin SE, Si H, Ormanoglu P, Carlson S, et al. Integrated Genomic and Functional microRNA Analysis Identifies miR-30-5p as a Tumor Suppressor and Potential Therapeutic Nanomedicine in Head and Neck Cancer. Clin Cancer Res. 2019;25:2860–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nishikura K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol. 2016;17:83–96.

    Article  CAS  PubMed  Google Scholar 

  28. Kawahara Y, Zinshteyn B, Sethupathy P, Iizasa H, Hatzigeorgiou AG, Nishikura K. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science. 2007;315:1137–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kume H, Hino K, Galipon J, Ui-Tei K. A-to-I editing in the miRNA seed region regulates target mRNA selection and silencing efficiency. Nucl Acids Res. 2014;42:10050–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang Y, Xu X, Yu S, Jeong KJ, Zhou Z, Han L, et al. Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers. Genome Res. 2017;27:1112–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Krepl M, Otyepka M, Banas P, Sponer J. Effect of guanine to inosine substitution on stability of canonical DNA and RNA duplexes: molecular dynamics thermodynamics integration study. J Phys Chem. 2013;117:1872–9.

    Article  CAS  Google Scholar 

  32. Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 2018;17:45.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Distefano R, Nigita G, Veneziano D, Romano G, Croce CM, Acunzo M. isoTar: Consensus Target Prediction with Enrichment Analysis for MicroRNAs Harboring Editing Sites and Other Variations. Methods Mol Biol. 2019;1970:211–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Viticchie G, Muller PAJ. c-Met and Other Cell Surface Molecules: Interaction, Activation and Functional Consequences. Biomedicines 2015;3:46–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang HM, Li L, Papadopoulou N, Hodgson G, Evans E, Galbraith M, et al. Mitogen-induced recruitment of ERK and MSK to SRE promoter complexes by ternary complex factor Elk-1. Nucl Acids Res. 2008;36:2594–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cavigelli M, Dolfi F, Claret FX, Karin M. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. EMBO J. 1995;14:5957–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Errico MC, Felicetti F, Bottero L, Mattia G, Boe A, Felli N, et al. The abrogation of the HOXB7/PBX2 complex induces apoptosis in melanoma through the miR-221&222-c-FOS pathway. Int J Cancer. 2013;133:879–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Whitmarsh AJ, Davis RJ. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl). 1996;74:589–607.

    Article  CAS  PubMed  Google Scholar 

  39. Iavarone C, Catania A, Marinissen MJ, Visconti R, Acunzo M, Tarantino C, et al. The platelet-derived growth factor controls c-myc expression through a JNK- and AP-1-dependent signaling pathway. J Biol Chem. 2003;278:50024–30.

    Article  CAS  PubMed  Google Scholar 

  40. Vartanian R, Masri J, Martin J, Cloninger C, Holmes B, Artinian N, et al. AP-1 regulates cyclin D1 and c-MYC transcription in an AKT-dependent manner in response to mTOR inhibition: role of AIP4/Itch-mediated JUNB degradation. Mol Cancer Res. 2011;9:115–30.

    Article  CAS  PubMed  Google Scholar 

  41. Baldacci S, Kherrouche Z, Cockenpot V, Stoven L, Copin MC, Werkmeister E, et al. MET amplification increases the metastatic spread of EGFR-mutated NSCLC. Lung Cancer. 2018;125:57–67.

    Article  PubMed  Google Scholar 

  42. Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Disco. 2014;4:1046–61.

    Article  CAS  Google Scholar 

  43. Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:5900–9.

    Article  CAS  PubMed  Google Scholar 

  44. Ferrer I, Zugazagoitia J, Herbertz S, John W, Paz-Ares L, Schmid-Bindert G. KRAS-Mutant non-small cell lung cancer: From biology to therapy. Lung Cancer. 2018;124:53–64.

    Article  PubMed  Google Scholar 

  45. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, et al. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009;15:489–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958–67.

    Article  CAS  PubMed  Google Scholar 

  47. Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9:154–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wu SG, Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 2018;17:38.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Magee P, Shi L, Garofalo M. Role of microRNAs in chemoresistance. Ann Transl Med. 2015;3:332.

    PubMed  PubMed Central  Google Scholar 

  50. Costa Cruz PH, Kato Y, Nakahama T, Shibuya T, Kawahara Y. A comparative analysis of ADAR mutant mice reveals site-specific regulation of RNA editing. RNA. 2020;26:454–69.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Vesely C, Tauber S, Sedlazeck FJ, Tajaddod M, von Haeseler A, Jantsch MF. ADAR2 induces reproducible changes in sequence and abundance of mature microRNAs in the mouse brain. Nucl Acids Res. 2014;42:12155–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Deng L, Vallega KA, Zhang S, Shi P, Sun SY. MET inhibition downregulates DR4 expression in MET-amplified lung cancer cells with acquired resistance to EGFR inhibitors through suppressing AP-1-mediated transcription. Neoplasia. 2021;23:766–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mauer J, Luo X, Blanjoie A, Jiao X, Grozhik AV, Patil DP, et al. Reversible methylation of m(6)A(m) in the 5’ cap controls mRNA stability. Nature. 2017;541:371–5.

    Article  CAS  PubMed  Google Scholar 

  54. Martinelli E, Morgillo F, Troiani T, Ciardiello F. Cancer resistance to therapies against the EGFR-RAS-RAF pathway: The role of MEK. Cancer Treat Rev. 2017;53:61–9.

    Article  CAS  PubMed  Google Scholar 

  55. Hua H, Kong Q, Yin J, Zhang J, Jiang Y. Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy. J Hematol Oncol. 2020;13:64.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Sierra JR, Cepero V, Giordano S. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy. Mol Cancer. 2010;9:75.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018;17:58.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Acunzo M, Romano G, Nigita G, Veneziano D, Fattore L, Lagana A, et al. Selective targeting of point-mutated KRAS through artificial microRNAs. Proc Natl Acad Sci. 2017;114:E4203–E12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Romano G, Nigita G, Calore F, Saviana M, Le P, Croce CM, et al. MiR-124a Regulates Extracellular Vesicle Release by Targeting GTPase Rabs in Lung Cancer. Front Oncol. 2020;10:1454.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Rehmsmeier M, Steffen P, Hochsmann M, Giegerich R. Fast and effective prediction of microRNA/target duplexes. RNA. 2004;10:1507–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the Virginia Commonwealth University Flow Cytometry Shared Resource, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059. We thank Dr. Theresa Swift-Scanlan for performing nCounter PanCancer Pathways Panel.

Funding

This work was supported by grants from the National Institutes of Health (NCI NCATS 5KL2TR002648), 1P20CA252717-01A1, and the American Lung Association (LCDA-922902).

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  1. These authors contributed equally: Giulia Romano, Patricia Le.

Authors and Affiliations

  1. Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Giulia Romano, Patricia Le, Michela Saviana, Lavender Micalo, Daniel del Valle Morales, Howard Li, Patrick Nana-Sinkam & Mario Acunzo

  2. Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA

    Giovanni Nigita & Francesca Lovat

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Contributions

GR and MA designed the study. GR, PL, GN, MS, LM, FL, and DDVM coordinated and performed the experiments, and analyzed the corresponding results. GR, PL, and MA wrote the manuscript. All authors contributed to editing the manuscript.

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Correspondence to Mario Acunzo.

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Romano, G., Le, P., Nigita, G. et al. A-to-I edited miR-411-5p targets MET and promotes TKI response in NSCLC-resistant cells. Oncogene 42, 1597–1606 (2023). https://doi.org/10.1038/s41388-023-02673-y

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