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Anexelekto (AXL) no more: microRNA-155 (miR-155) controls the “Uncontrolled” in SARS-CoV-2

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Abstract

AXL is the gene that encodes the Anexelekto (AXL) receptor tyrosine kinase that demonstrates significant roles in various cellular processes, including cell growth, survival, and migration. Anexelekto is a Greek word meaning excessive and uncontrolled, semantically implying the crucial involvement of AXL in cancer and immune biology, and in promoting cancer metastasis. AXL overexpression appears to drive epithelial to mesenchymal transition, tumor angiogenesis, decreased antitumor immune response, and resistance to therapeutic agents. Recently, AXL has been reported to play important roles in several viral infections, including SARS-CoV-2. We have previously outlined the importance of microRNAs (miRNAs, miRs) and especially miR-155 in SARS-CoV-2 pathophysiology through regulation of the Renin–Angiotensin Aldosterone System (RAAS) and influence on several aspects of host innate immunity. MiRNAs are negative regulators of gene expression, decreasing the stability of target RNAs or limiting their translation and, enthrallingly, miR-155 is also involved in AXL homeostasis—both endogenously and pharmaceutically using repurposed drugs (e.g., metformin)—highlighting thrifty evolutionary host innate immunity mechanisms that successfully can thwart viral entry and replication. Cancer, infections, and immune system disturbances will increasingly involve miRNA diagnostics and therapeutics in the future.

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References

  1. Worldodometer. https://www.worldometers.info/coronavirus/. Accessed 2023–11–22 2023.

  2. Zhang Q, Xiang R, Huo S, Zhou Y, Jiang S, Wang Q, et al. Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy. Signal Transduct Target Ther. 2021;6(1):233. https://doi.org/10.1038/s41392-021-00653-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lei M, Ma Y, Chen H, Huang P, Sun J, Wang X, et al. Emerging SARS-CoV-2 variants of concern potentially expand host range to chickens: insights from AXL, NRP1 and ACE2 receptors. Virol J. 2023;20(1):196. https://doi.org/10.1186/s12985-023-02123-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Papadopoulos KI, Papadopoulou A, Aw TC. A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children. Hum Cell. 2023;36(1):26–40. https://doi.org/10.1007/s13577-022-00819-w.

    Article  CAS  PubMed  Google Scholar 

  5. Papadopoulos KI, Papadopoulou A, Aw TC. Beauty and the beast: host microRNA-155 versus SARS-CoV-2. Hum Cell. 2023;36(3):908–22. https://doi.org/10.1007/s13577-023-00867-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Papadopoulos KI, Sutheesophon W, Manipalviratn S, Aw TC. Age and genotype dependent erythropoietin protection in COVID-19. World J Stem Cells. 2021;13(10):1513–29. https://doi.org/10.4252/wjsc.v13.i10.1513.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wang S, Qiu Z, Hou Y, Deng X, Xu W, Zheng T, et al. AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells. Cell Res. 2021;31(2):126–40. https://doi.org/10.1038/s41422-020-00460-y.

    Article  CAS  PubMed  Google Scholar 

  8. Ghosh RS. TAM receptors: A phosphatidylserine receptor family and its implications in viral infections. Int Rev Cell Mol Biol. 2020;357:81–122. https://doi.org/10.1016/bs.ircmb.2020.09.003.

    Article  CAS  Google Scholar 

  9. Zhu C, Wei Y, Wei X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. 2019;18(1):153. https://doi.org/10.1186/s12943-019-1090-3.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol. 2008;8(5):327–36. https://doi.org/10.1038/nri2303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Goyette MA, Côté JF. AXL receptor tyrosine kinase as a promising therapeutic target directing multiple aspects of cancer progression and metastasis. Cancers (Basel). 2022. https://doi.org/10.3390/cancers14030466.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Perera-Lecoin M, Meertens L, Carnec X, Amara A. Flavivirus entry receptors: an update. Viruses. 2013;6(1):69–88. https://doi.org/10.3390/v6010069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bhattacharyya S, Zagórska A, Lew ED, Shrestha B, Rothlin CV, Naughton J, et al. Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe. 2013;14(2):136–47. https://doi.org/10.1016/j.chom.2013.07.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gay CM, Balaji K, Byers LA. Giving AXL the axe: targeting AXL in human malignancy. Br J Cancer. 2017;116(4):415–23. https://doi.org/10.1038/bjc.2016.428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ravichandran KS. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity. 2011;35(4):445–55. https://doi.org/10.1016/j.immuni.2011.09.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shimojima M, Ikeda Y, Kawaoka Y. The mechanism of Axl-mediated Ebola virus infection. J Infect Dis. 2007;196(Suppl 2):S259–63. https://doi.org/10.1086/520594.

    Article  CAS  PubMed  Google Scholar 

  17. Shimojima M, Takada A, Ebihara H, Neumann G, Fujioka K, Irimura T, et al. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol. 2006;80(20):10109–16. https://doi.org/10.1128/jvi.01157-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression analysis highlights axl as a candidate zika virus entry receptor in neural stem cells. Cell Stem Cell. 2016;18(5):591–6. https://doi.org/10.1016/j.stem.2016.03.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bohan D, Van Ert H, Ruggio N, Rogers KJ, Badreddine M, Aguilar Briseño JA, et al. Phosphatidylserine receptors enhance SARS-CoV-2 infection. PLoS Pathog. 2021;17(11): e1009743. https://doi.org/10.1371/journal.ppat.1009743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Meertens L, Carnec X, Lecoin MP, Ramdasi R, Guivel-Benhassine F, Lew E, et al. The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe. 2012;12(4):544–57. https://doi.org/10.1016/j.chom.2012.08.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ning K, Zou W, Xu P, Cheng F, Zhang EY, Zhang-Chen A, et al. Identification of AXL as a co-receptor for human parvovirus B19 infection of human erythroid progenitors. Sci Adv. 2023;9(2):eade0869. https://doi.org/10.1126/sciadv.ade0869.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Rizzi M, Tonello S, D’Onghia D, Sainaghi PP. Gas6/TAM Axis Involvement in modulating inflammation and fibrosis in covid-19 patients. Int J Mol Sci. 2023. https://doi.org/10.3390/ijms24020951.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Boytz R, Słabicki M, Ramaswamy S, Patten JJ, Zou C, Meng C, et al. Anti-SARS-CoV-2 activity of targeted kinase inhibitors: repurposing clinically available drugs for COVID-19 therapy. J Med Virol. 2023;95(1): e28157. https://doi.org/10.1002/jmv.28157.

    Article  CAS  PubMed  Google Scholar 

  24. Papadopoulos KI, Wattanaarsakit P, Prasongchean W, Narain R. 10 - Gene therapies in clinical trials. In: Narain R, editor. polymers and nanomaterials for gene therapy. Woodhead Publishing; 2016. p. 231–56.

    Chapter  Google Scholar 

  25. Plotnikova O, Baranova A, Skoblov M. Comprehensive analysis of human microrna-mrna interactome. Front Genet. 2019;10:933. https://doi.org/10.3389/fgene.2019.00933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mishra R, Kumar A, Ingle H, Kumar H. The interplay between viral-derived mirnas and host immunity during infection. Front Immunol. 2020. https://doi.org/10.3389/fimmu.2019.03079.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Papadopoulos KI, Papadopoulou A, Aw TC. MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation: implications for innovative type 2 diabetes mellitus management. World J Diabetes. 2023;14(9):1334–40. https://doi.org/10.4239/wjd.v14.i9.1334.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Masaki T, Arend KC, Li Y, Yamane D, McGivern DR, Kato T, et al. miR-122 stimulates hepatitis C virus RNA synthesis by altering the balance of viral RNAs engaged in replication versus translation. Cell Host Microbe. 2015;17(2):217–28. https://doi.org/10.1016/j.chom.2014.12.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schult P, Roth H, Adams RL, Mas C, Imbert L, Orlik C, et al. microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site. Nat Commun. 2018;9(1):2613. https://doi.org/10.1038/s41467-018-05053-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kalkusova K, Taborska P, Stakheev D, Smrz D. The role of mir-155 in antitumor immunity. Cancers (Basel). 2022. https://doi.org/10.3390/cancers14215414.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chatzopoulou F, Kyritsis KA, Papagiannopoulos CI, Galatou E, Mittas N, Theodoroula NF, et al. Dissecting mirna-gene networks to map clinical utility roads of pharmacogenomics-guided therapeutic decisions in cardiovascular precision medicine. Cells. 2022;11(4):607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cortez MA, Anfossi S, Ramapriyan R, Menon H, Atalar SC, Aliru M, et al. Role of miRNAs in immune responses and immunotherapy in cancer. Genes Chromosom Cancer. 2019;58(4):244–53. https://doi.org/10.1002/gcc.22725.

    Article  CAS  PubMed  Google Scholar 

  33. Hou Y, Wang J, Wang X, Shi S, Wang W, Chen Z. Appraising microrna-155 as a noninvasive diagnostic biomarker for cancer detection: a meta-analysis. Medicine (Baltim). 2016;95(2): e2450. https://doi.org/10.1097/md.0000000000002450.

    Article  CAS  Google Scholar 

  34. Dudda Jan C, Salaun B, Ji Y, Palmer Douglas C, Monnot Gwennaelle C, Merck E, et al. MicroRNA-155 is required for effector CD8<sup>+</sup> T Cell responses to virus infection and cancer. Immunity. 2013;38(4):742–53. https://doi.org/10.1016/j.immuni.2012.12.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jafarzadeh A, Naseri A, Shojaie L, Nemati M, Jafarzadeh S, Bannazadeh Baghi H, et al. MicroRNA-155 and antiviral immune responses. Int Immunopharmacol. 2021;101(Pt A): 108188. https://doi.org/10.1016/j.intimp.2021.108188.

    Article  CAS  PubMed  Google Scholar 

  36. Papadopoulos KI, Sutheesophon W, Manipalviratn S, Aw TC. A southeast asian perspective on the COVID-19 Pandemic: Hemoglobin E (HbE)-trait confers resistance against COVID-19. Med Sci Monit Basic Res. 2021;27: e929207. https://doi.org/10.12659/MSMBR.929207.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Rai KR, Liao Y, Cai M, Qiu H, Wen F, Peng M, et al. MIR155HG plays a bivalent role in regulating innate antiviral immunity by encoding long noncoding RNA-155 and microRNA-155–5p. MBio. 2022;13(6):e0251022. https://doi.org/10.1128/mbio.02510-22.

    Article  CAS  PubMed  Google Scholar 

  38. de Miguel-Pérez D, Bayarri-Lara CI, Ortega FG, Russo A, Moyano Rodriguez MJ, Alvarez-Cubero MJ, et al. Post-surgery circulating tumor cells and AXL overexpression as new poor prognostic biomarkers in resected lung adenocarcinoma. Cancers (Basel). 2019. https://doi.org/10.3390/cancers11111750.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kurowska-Stolarska M, Ballantine L, Stolarski B, Hunter J, Hueber A, Gracie A, et al. miR155 and miR34a regulate proinflammatory cytokine production by human monocytes. Ann of The Rheum Dis - ANN RHEUM DIS. 2010. https://doi.org/10.1136/ard.2010.129619g.

    Article  Google Scholar 

  40. Yin Z, Herron S, Silveira S, Kleemann K, Gauthier C, Mallah D, et al. Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer’s disease. Nat Neurosci. 2023;26(7):1196–207. https://doi.org/10.1038/s41593-023-01355-y.

    Article  CAS  PubMed  Google Scholar 

  41. Sun CY, Zhang XP, Liu F, Wang W. Orchestration of lincRNA-p21 and miR-155 in modulating the adaptive dynamics of HIF-1α. Front Genet. 2020;11:871. https://doi.org/10.3389/fgene.2020.00871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu C, Zhang J-W, Hu L, Song Y-C, Zhou L, Fan Y, et al. Activation of the AT1R/HIF-1a/ACE axis mediates angiotensin ii-induced VEGF synthesis in mesenchymal stem cells. Biomed Res Int. 2014;2014: 627380. https://doi.org/10.1155/2014/627380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shao S, Zhao L, An G, Zhang L, Jing X, Luo M, et al. Metformin suppresses HIF-1α expression in cancer-associated fibroblasts to prevent tumor-stromal cross talk in breast cancer. Faseb j. 2020;34(8):10860–70. https://doi.org/10.1096/fj.202000951RR.

    Article  CAS  PubMed  Google Scholar 

  44. Hart PC, Kenny HA, Grassl N, Watters KM, Litchfield LM, Coscia F, et al. Mesothelial cell HIF1α expression is metabolically downregulated by metformin to prevent oncogenic tumor-stromal crosstalk. Cell Rep. 2019;29(12):4086-98.e6. https://doi.org/10.1016/j.celrep.2019.11.079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ye J, Chen K, Qi L, Li R, Tang H, Zhou C, et al. Metformin suppresses hypoxia-induced migration via the HIF-1α/VEGF pathway in gallbladder cancer in vitro and in vivo. Oncol Rep. 2018;40(6):3501–10. https://doi.org/10.3892/or.2018.6751.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang WN, Li XP, Wang PF, Zhu L, Xiao XH, Dai YJ. Comprehensive analysis of the novel omicron receptor AXL in cancers. Comput Struct Biotechnol J. 2022;20:3304–12. https://doi.org/10.1016/j.csbj.2022.06.051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Patel B, Chapman SA, Neumann JT, Visaria A, Ogungbe O, Wen S, et al. Outcomes of patients with active cancers and pre-existing cardiovascular diseases infected with SARS-CoV-2. Cardiooncology. 2023;9(1):36. https://doi.org/10.1186/s40959-023-00187-w.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Vijenthira A, Gong IY, Fox TA, Booth S, Cook G, Fattizzo B, et al. Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients. Blood. 2020;136(25):2881–92. https://doi.org/10.1182/blood.2020008824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. San Martín-López JV, Mesa N, Bernal-Bello D, Morales-Ortega A, Rivilla M, Guerrero M, et al. Seven epidemic waves of COVID-19 in a hospital in madrid: analysis of severity and associated factors. Viruses. 2023. https://doi.org/10.3390/v15091839.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ivanov N, Krastev B, Miteva DG, Batselova H, Alexandrova R, Velikova T. Effectiveness and safety of COVID-19 vaccines in patients with oncological diseases: State-of-the-art. World J Clin Oncol. 2023;14(9):343–56. https://doi.org/10.5306/wjco.v14.i9.343.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Harmonizome. 2023. https://maayanlab.cloud/Harmonizome/gene_set/hsa-miR-155-5p/MiRTarBase+microRNA+Targets. Accessed 2023–10–17 2023.

  52. Hsu SD, Tseng YT, Shrestha S, Lin YL, Khaleel A, Chou CH, miRTarBase update, et al. An information resource for experimentally validated miRNA-target interactions. Nucleic Acids Res. 2014;2014(42 (Database issue):D):78–85. https://doi.org/10.1093/nar/gkt1266.

    Article  CAS  Google Scholar 

  53. Taylor CT, Scholz CC. The effect of HIF on metabolism and immunity. Nat Rev Nephrol. 2022;18(9):573–87. https://doi.org/10.1038/s41581-022-00587-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kunej T. Integrative map of HIF-1A regulatory elements and variations. Genes (Basel). 2021. https://doi.org/10.3390/genes12101526.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zhang R, Wu Y, Zhao M, Liu C, Zhou L, Shen S, et al. Role of HIF-1alpha in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2009;297(4):L631–40. https://doi.org/10.1152/ajplung.90415.2008.

    Article  CAS  PubMed  Google Scholar 

  56. Serocki M, Bartoszewska S, Janaszak-Jasiecka A, Ochocka RJ, Collawn JF, Bartoszewski R. miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target. Angiogenesis. 2018;21(2):183–202. https://doi.org/10.1007/s10456-018-9600-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. He B, Hu M, Liang Z, Ma Q, Zi Y, Dong Z, et al. Efficacy of shenqi pollen capsules for high-altitude deacclimatization syndrome via suppression of the reoxygenation injury and inflammatory response. J Immunol Res. 2019;2019:4521231. https://doi.org/10.1155/2019/4521231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yang D, Wang J, Xiao M, Zhou T, Shi X. Role of Mir-155 in controlling HIF-1α level and promoting endothelial cell maturation. Sci Rep. 2016;6:35316. https://doi.org/10.1038/srep35316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jelkmann W. Molecular biology of erythropoietin. Intern Med. 2004;43(8):649–59. https://doi.org/10.2169/internalmedicine.43.649.

    Article  CAS  PubMed  Google Scholar 

  60. Castillo-Uribe VA, Cucho-Vásquez BM, Contreras-León ZL, Accinelli RA, Huayanay-Falconi L, Chu-Rivera FR. Effect of altitude on COVID-19 mortality rate and case incidence in Peru, the country with the highest cumulative mortality rate worldwide. J Public Health. 2023. https://doi.org/10.1007/s10389-023-02104-y.

    Article  Google Scholar 

  61. Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014;111(37):13373–8. https://doi.org/10.1073/pnas.1404848111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Goyette MA, Elkholi IE, Apcher C, Kuasne H, Rothlin CV, Muller WJ, et al. Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels. Proc Natl Acad Sci U S A. 2021. https://doi.org/10.1073/pnas.2023868118.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Yang LG, Cao MZ, Zhang J, Li XY, Sun QL. LncRNA XIST modulates HIF-1A/AXL signaling pathway by inhibiting miR-93-5p in colorectal cancer. Mol Genet Genomic Med. 2020;8(4): e1112. https://doi.org/10.1002/mgg3.1112.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Triggle CR, Mohammed I, Bshesh K, Marei I, Ye K, Ding H, et al. Metformin: is it a drug for all reasons and diseases? Metabolism. 2022;133: 155223. https://doi.org/10.1016/j.metabol.2022.155223.

    Article  CAS  PubMed  Google Scholar 

  65. Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential. Nat Rev Endocrinol. 2023;19(8):460–76. https://doi.org/10.1038/s41574-023-00833-4.

    Article  CAS  PubMed  Google Scholar 

  66. Papadopoulos KI, Sutheesophon W, Aw TC. Too hard to die: exercise training mediates specific and immediate SARS-CoV-2 protection. World J Virol. 2022;11(2):98–103. https://doi.org/10.5501/wjv.v11.i2.98.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Saito T, Itoh M, Tohda S. Metformin suppresses the growth of leukemia cells partly through downregulation of AXL receptor tyrosine kinase. Leuk Res. 2020;94: 106383. https://doi.org/10.1016/j.leukres.2020.106383.

    Article  CAS  PubMed  Google Scholar 

  68. Gayatri MB, Kancha RK, Patchva D, Velugonda N, Gundeti S, Reddy ABM. Metformin exerts antileukemic effects by modulating lactate metabolism and overcomes imatinib resistance in chronic myelogenous leukemia. FEBS J. 2023;290(18):4480–95. https://doi.org/10.1111/febs.16818.

    Article  CAS  PubMed  Google Scholar 

  69. Hong J, Maacha S, Pidkovka N, Bates A, Salaria SN, Washington MK, et al. AXL promotes metformin-induced apoptosis through mediation of autophagy by activating ROS-AMPK-ULK1 signaling in human esophageal adenocarcinoma. Front Oncol. 2022;12: 903874. https://doi.org/10.3389/fonc.2022.903874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kim NY, Lee HY, Lee C. Metformin targets Axl and Tyro3 receptor tyrosine kinases to inhibit cell proliferation and overcome chemoresistance in ovarian cancer cells. Int J Oncol. 2015;47(1):353–60. https://doi.org/10.3892/ijo.2015.3004.

    Article  CAS  PubMed  Google Scholar 

  71. Tossetta G. Metformin improves ovarian cancer sensitivity to paclitaxel and platinum-based drugs: a review of in vitro findings. Int J Mol Sci. 2022;23(21):12893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Shi H, Sun Y, He M, Yang X, Hamada M, Fukunaga T, et al. Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression. Oncog. 2020;39(3):530–45. https://doi.org/10.1038/s41388-019-0962-8.

    Article  CAS  Google Scholar 

  73. Bansal N, Mishra PJ, Stein M, DiPaola RS, Bertino JR. Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells. Oncotarget. 2015;6(17):15321–31. https://doi.org/10.18632/oncotarget.4148.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Fujimori T, Kato K, Fujihara S, Iwama H, Yamashita T, Kobayashi K, et al. Antitumor effect of metformin on cholangiocarcinoma: In vitro and in vivo studies. Oncol Rep. 2015;34(6):2987–96. https://doi.org/10.3892/or.2015.4284.

    Article  CAS  PubMed  Google Scholar 

  75. Atici Y, Baskol G, Bayram F. A new approach for the pleiotropic effect of metformin use in type 2 diabetes mellitus. Turk J of Biochem. 2022;47(6):775–82. https://doi.org/10.1515/tjb-2022-0013.

    Article  CAS  Google Scholar 

  76. Alimoradi N, Firouzabadi N, Fatehi R. How metformin affects various malignancies by means of microRNAs: a brief review. Cancer Cell Int. 2021;21(1):207. https://doi.org/10.1186/s12935-021-01921-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Petrovic AR, Jovanovic IP, Jurisevic MM, Jovanovic MZ, Jovanovic MM, Pavlovic SP, et al. Metformin promotes antitumor activity of NK cells via overexpression of miRNA-150 and miRNA-155. Am J Transl Res. 2023;15(4):2727–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Xia W, Qi X, Li M, Wu Y, Sun L, Fan X, et al. Metformin promotes anticancer activity of NK cells in a p38 MAPK dependent manner. Oncoimmunology. 2021;10(1):1995999. https://doi.org/10.1080/2162402x.2021.1995999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Trotta R, Chen L, Ciarlariello D, Josyula S, Mao C, Costinean S, et al. miR-155 regulates IFN-γ production in natural killer cells. Blood. 2012;119(15):3478–85. https://doi.org/10.1182/blood-2011-12-398099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gou L, Liu G, Ma R, Regmi A, Zeng T, Zheng J, et al. High fat-induced inflammation in vascular endothelium can be improved by Abelmoschus esculentus and metformin via increasing the expressions of miR-146a and miR-155. Nutr Metab (Lond). 2020;17:35. https://doi.org/10.1186/s12986-020-00459-7.

    Article  CAS  PubMed  Google Scholar 

  81. Amara VR, Surapaneni SK, Tikoo K. Metformin attenuates cardiovascular and renal injury in uninephrectomized rats on DOCA-salt: Involvement of AMPK and miRNAs in cardioprotection. Toxicol Appl Pharmacol. 2019;362:95–104. https://doi.org/10.1016/j.taap.2018.10.004.

    Article  CAS  PubMed  Google Scholar 

  82. Petrelli F, Grappasonni I, Nguyen CTT, Tesauro M, Pantanetti P, Xhafa S, et al. Metformin and Covid-19: a systematic review of systematic reviews with meta-analysis. Acta Biomed. 2023;94(S3): e2023138. https://doi.org/10.23750/abm.v94iS3.14405.

    Article  PubMed  Google Scholar 

  83. Martin DE, Cadar AN, Bartley JM. Old drug, new tricks: the utility of metformin in infection and vaccination responses to influenza and SARS-CoV-2 in older adults. Front Aging. 2023;4:1272336. https://doi.org/10.3389/fragi.2023.1272336.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Behrooz M, Hajjarzadeh S, Kahroba H, Ostadrahimi A, Bastami M. Expression pattern of miR-193a, miR122, miR155, miR-15a, and miR146a in peripheral blood mononuclear cells of children with obesity and their relation to some metabolic and inflammatory biomarkers. BMC Pediatr. 2023;23(1):95. https://doi.org/10.1186/s12887-023-03867-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dinesen S, El-Faitarouni A, Frisk NLS, Sørensen AE, Dalgaard LT. Circulating microRNA as biomarkers for gestational diabetes mellitus-a systematic review and meta-analysis. Int J Mol Sci. 2023. https://doi.org/10.3390/ijms24076186.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Bramante CT, Ingraham NE, Murray TA, Marmor S, Hovertsen S, Gronski J, et al. Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis. Lancet Healthy Longev. 2021;2(1):e34–41. https://doi.org/10.1016/s2666-7568(20)30033-7.

    Article  PubMed  Google Scholar 

  87. Postler TS, Peng V, Bhatt DM, Ghosh S. Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism. Sci Rep. 2021;11(1):18721. https://doi.org/10.1038/s41598-021-97441-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hsiao FC, Lin YF, Hsieh PS, Chu NF, Shieh YS, Hsieh CH, et al. Circulating growth arrest-specific 6 protein is associated with adiposity, systemic inflammation, and insulin resistance among overweight and obese adolescents. J Clin Endocrinol Metab. 2013;98(2):E267–74. https://doi.org/10.1210/jc.2012-3179.

    Article  CAS  PubMed  Google Scholar 

  89. McShane L, Tabas I, Lemke G, Kurowska-Stolarska M, Maffia P. TAM receptors in cardiovascular disease. Cardiovasc Res. 2019;115(8):1286–95. https://doi.org/10.1093/cvr/cvz100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lee CH, Changchien CY, Hung YJ. Targeting inflammation in type 2 diabetes by antibody-mediated Tyro-3, Axl. Mer receptor activation J Diabetes Investig. 2015;6(5):491–4. https://doi.org/10.1111/jdi.12351.

    Article  PubMed  Google Scholar 

  91. Wium M, Paccez JD, Zerbini LF. The dual role of TAM receptors in autoimmune diseases and cancer: an overview. Cells. 2018. https://doi.org/10.3390/cells7100166.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. THAI StemLife, 566/3 Soi Ramkhamhaeng 39 (Thepleela 1), Prachaouthit Rd, Wangthonglang, Bangkok, 10310, Thailand

    K. I. Papadopoulos

  2. Feelgood Lund, Occupational and Environmental Health Services, Ideon Science Park, Scheelevägen 17, 223 63, Lund, Sweden

    A. Papadopoulou

  3. Department of Laboratory Medicine, Changi General Hospital, 2 Simei Street 3, Singapore, 529889, Singapore

    T. C. Aw

  4. Department of Medicine, National University of Singapore, Singapore, 119228, Singapore

    T. C. Aw

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  3. T. C. Aw
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Dr Konstantinos I. Papadopoulos conceived and conceptualized the argumentation, designed the layout, drafted the initial manuscript, and reviewed and revised the manuscript. Dr Alexandra Papadopoulou performed the literature search, extracted vital information, contributed to the synthesis of the work, and reviewed and revised the manuscript. Dr Tar-Choon Aw coordinated and supervised literature search, made substantial and direct intellectual contributions and critically reviewed the manuscript for important intellectual content. All authors approved the submitted final manuscript and agree to be accountable for all aspects of the work.

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Papadopoulos, K.I., Papadopoulou, A. & Aw, T.C. Anexelekto (AXL) no more: microRNA-155 (miR-155) controls the “Uncontrolled” in SARS-CoV-2. Human Cell 37, 582–592 (2024). https://doi.org/10.1007/s13577-024-01041-6

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