MicroRNA controls of cellular senescence

  • Suh, Nayoung (Department of Pharmaceutical Engineering, Soon Chun Hyang University)
  • Received : 2018.08.06
  • Published : 2018.10.31


Cellular senescence is a state of permanent cell-cycle arrest triggered by different internal and external stimuli. This phenomenon is considered to be both beneficial and detrimental depending on the cell types and biological contexts. During normal embryonic development and after tissue injury, cellular senescence is critical for tissue remodeling. In addition, this process is useful for arresting growth of tumor cells, particularly during early onset of tumorigenesis. However, accumulation of senescent cells decreases tissue regenerative capabilities and induces inflammation, which is responsible for cancer and organismal aging. Therefore cellular senescence has to be tightly regulated, and dysregulation might lead to the aging and human diseases. Among many regulators of cellular senescence, in this review, I will focus on microRNAs, small non-coding RNAs playing critical roles in diverse biological events including cellular senescence.


Cellular senescence;MicroRNAs;Networks;Regulatory pathways


Supported by : Soon Chun Hyang University, National Research Foundation of Korea (NRF)


  1. Farh KK, Grimson A, Jan C et al (2005) The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310, 1817-1821
  2. Davalos AR, Coppe JP, Campisi J and Desprez PY (2010) Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev 29, 273-283
  3. Turinetto V, Vitale E and Giachino C (2016) Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy. Int J Mol Sci 17, pii. E1164
  4. Banfi A, Muraglia A, Dozin B, Mastrogiacomo M, Cancedda R and Quarto R (2000) Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: Implications for their use in cell therapy. Exp Hematol 28, 707-715
  5. Cheng H, Qiu L, Ma J et al (2011) Replicative senescence of human bone marrow and umbilical cord derived mesenchymal stem cells and their differentiation to adipocytes and osteoblasts. Mol Biol Rep 38, 5161-5168
  6. Kim M, Kim C, Choi YS, Kim M, Park C and Suh Y (2012) Age-related alterations in mesenchymal stem cells related to shift in differentiation from osteogenic to adipogenic potential: implication to age-associated bone diseases and defects. Mech Ageing Dev 133, 215-225
  7. Sepulveda JC, Tome M, Fernandez ME et al (2014) Cell senescence abrogates the therapeutic potential of human mesenchymal stem cells in the lethal endotoxemia model. Stem Cells 32, 1865-1877
  8. Geissler S, Textor M, Kuhnisch J et al (2012) Functional comparison of chronological and in vitro aging: differential role of the cytoskeleton and mitochondria in mesenchymal stromal cells. PLoS One 7, e52700
  9. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136, 215-233
  10. Suh N and Blelloch R (2011) Small RNAs in early mammalian development: from gametes to gastrulation. Development 138, 1653-1661
  11. Childs BG, Baker DJ, Kirkland JL, Campisi J and van Deursen JM (2014) Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep 15, 1139-1153
  12. Rajagopalan S and Long EO (2012) Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proc Natl Acad Sci U S A 109, 20596-20601
  13. Munoz-Espin D, Canamero M, Maraver A et al (2013) Programmed cell senescence during mammalian embryonic development. Cell 155, 1104-1118
  14. Storer M, Mas A, Robert-Moreno A et al (2013) Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119-1130
  15. Collado M and Serrano M (2010) Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 10, 51-57
  16. Jun JI and Lau LF (2010) Cellular senescence controls fibrosis in wound healing. Aging (Albany NY) 2, 627-631
  17. Kong X, Feng D, Wang H et al (2012) Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 56, 1150-1159
  18. Lecot P, Alimirah F, Desprez PY, Campisi J and Wiley C (2016) Context-dependent effects of cellular senescence in cancer development. Br J Cancer 114, 1180-1184
  19. Coppe JP, Patil CK, Rodier F et al (2008) Senescenceassociated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6, 2853-2868
  20. Kuilman T, Michaloglou C, Vredeveld LC et al (2008) Oncogene-induced senescence relayed by an interleukin dependent inflammatory network. Cell 133, 1019-1031
  21. Herbig U, Jobling WA, Chen BP, Chen DJ and Sedivy JM (2004) Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 14, 501-513
  22. Petrova NV, Velichko AK, Razin SV and Kantidze OL (2016) Small molecule compounds that induce cellular senescence. Aging Cell 15, 999-1017
  23. Munoz-Espin D and Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15, 482-496
  24. Serrano M, Lin AW, McCurrach ME, Beach D and Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602
  25. Lu T and Finkel T (2008) Free radicals and senescence. Exp Cell Res 314, 1918-1922
  26. Wiley CD, Velarde MC, Lecot P et al (2016) Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype. Cell Metab 23, 303-314
  27. Bent EH, Gilbert LA and Hemann MT (2016) A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev 30, 1811-1821
  28. Lee BY, Han JA, Im JS et al (2006) Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell 5, 187-195
  29. Lowe SW, Cepero E and Evan G (2004) Intrinsic tumour suppression. Nature 432, 307-315
  30. Hayflick L and Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25, 585-621
  31. Hayflick L (1965) The Limited in Vitro Lifetime of Human Diploid Cell Strains. Exp Cell Res 37, 614-636
  32. Yamakuchi M, Ferlito M and Lowenstein CJ (2008) miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci U S A 105, 13421-13426
  33. Cui H, Ge J, Xie N et al (2017) miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence. Am J Respir Cell Mol Biol 56, 168-178
  34. Bai XY, Ma Y, Ding R, Fu B, Shi S and Chen XM (2011) miR-335 and miR-34a Promote renal senescence by suppressing mitochondrial antioxidative enzymes. J Am Soc Nephrol 22, 1252-1261
  35. Jazbutyte V, Fiedler J, Kneitz S et al (2013) MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age (Dordr) 35, 747-762
  36. Subramanyam D and Blelloch R (2011) From microRNAs to targets: pathway discovery in cell fate transitions. Curr Opin Genet Dev 21, 498-503
  37. Maes OC, Sarojini H and Wang E (2009) Stepwise up-regulation of microRNA expression levels from replicating to reversible and irreversible growth arrest states in WI-38 human fibroblasts. J Cell Physiol 221, 109-119
  38. Campisi J and d'Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8, 729-740
  39. Collado M, Blasco MA and Serrano M (2007) Cellular senescence in cancer and aging. Cell 130, 223-233
  40. Kuilman T, Michaloglou C, Mooi WJ and Peeper DS (2010) The essence of senescence. Genes Dev 24, 2463-2479
  41. Hernandez-Segura A, Nehme J and Demaria M (2018) Hallmarks of Cellular Senescence. Trends Cell Biol 28, 436-453
  42. Sharpless NE and Sherr CJ (2015) Forging a signature of in vivo senescence. Nat Rev Cancer 15, 397-408
  43. Wang Y, Scheiber MN, Neumann C, Calin GA and Zhou D (2011) MicroRNA regulation of ionizing radiationinduced premature senescence. Int J Radiat Oncol Biol Phys 81, 839-848
  44. Dhahbi JM, Atamna H, Boffelli D, Magis W, Spindler SR and Martin DI (2011) Deep sequencing reveals novel microRNAs and regulation of microRNA expression during cell senescence. PLoS One 6, e20509
  45. Hu W, Chan CS, Wu R et al (2010) Negative regulation of tumor suppressor p53 by microRNA miR-504. Mol Cell 38, 689-699
  46. Le MT, Teh C, Shyh-Chang N et al (2009) MicroRNA-125b is a novel negative regulator of p53. Genes Dev 23, 862-876
  47. Kumar M, Lu Z, Takwi AA et al (2011) Negative regulation of the tumor suppressor p53 gene by microRNAs. Oncogene 30, 843-853
  48. Pichiorri F, Suh SS, Rocci A et al (2010) Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell 18, 367-381
  49. Xiao J, Lin H, Luo X, Luo X and Wang Z (2011) miR-605 joins p53 network to form a p53:miR-605:Mdm2 positive feedback loop in response to stress. EMBO J 30, 5021
  50. Luo J, Nikolaev AY, Imai S et al (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107, 137-148
  51. Zhao T, Li J and Chen AF (2010) MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. Am J Physiol Endocrinol Metab 299, E110-116
  52. Ito T, Yagi S and Yamakuchi M (2010) MicroRNA-34a regulation of endothelial senescence. Biochem Biophys Res Commun 398, 735-740
  53. Yi C, Wang Q, Wang L et al (2012) MiR-663, a microRNA targeting p21(WAF1/CIP1), promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma. Oncogene 31, 4421-4433
  54. Abdelmohsen K, Srikantan S, Tominaga K et al (2012) Growth inhibition by miR-519 via multiple p21-inducing pathways. Mol Cell Biol 32, 2530-2548
  55. Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D and Barrett JC (1996) Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A 93, 13742-13747
  56. Di Micco R, Fumagalli M, Cicalese A et al (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638-642
  57. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K and Carson DA (1994) Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368, 753-756
  58. Stone S, Jiang P, Dayananth P et al (1995) Complex structure and regulation of the P16 (MTS1) locus. Cancer Res 55, 2988-2994
  59. Lal A, Kim HH, Abdelmohsen K et al (2008) p16(INK4a) translation suppressed by miR-24. PLoS One 3, e1864
  60. Xu D, Takeshita F, Hino Y et al (2011) miR-22 represses cancer progression by inducing cellular senescence. J Cell Biol 193, 409-424
  61. Rivetti di Val Cervo P, Lena AM, Nicoloso M et al (2012) p63-microRNA feedback in keratinocyte senescence. Proc Natl Acad Sci U S A 109, 1133-1138
  62. Marasa BS, Srikantan S, Martindale JL et al (2010) MicroRNA profiling in human diploid fibroblasts uncovers miR-519 role in replicative senescence. Aging (Albany NY) 2, 333-343
  63. Humbert PO, Verona R, Trimarchi JM, Rogers C, Dandapani S and Lees JA (2000) E2f3 is critical for normal cellular proliferation. Genes Dev 14, 690-703
  64. Ren XS, Yin MH, Zhang X et al (2014) Tumor-suppressive microRNA-449a induces growth arrest and senescence by targeting E2F3 in human lung cancer cells. Cancer Lett 344, 195-203
  65. Menghini R, Casagrande V, Cardellini M et al (2009) MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation 120, 1524-1532
  66. Bou Kheir T, Futoma-Kazmierczak E, Jacobsen A et al (2011) miR-449 inhibits cell proliferation and is downregulated in gastric cancer. Mol Cancer 10, 29
  67. Okada M, Kim HW, Matsu-ura K, Wang YG, Xu M and Ashraf M (2016) Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase. Stem Cells 34, 148-159
  68. Lou Z, Minter-Dykhouse K, Franco S et al (2006) MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol Cell 21, 187-200
  69. Lee JH, Park SJ, Jeong SY et al (2015) MicroRNA-22 Suppresses DNA Repair and Promotes Genomic Instability through Targeting of MDC1. Cancer Res 75, 1298-1310
  70. Borgdorff V, Lleonart ME, Bishop CL et al (2010) Multiple microRNAs rescue from Ras-induced senescence by inhibiting p21(Waf1/Cip1). Oncogene 29, 2262-2271
  71. Li G, Luna C, Qiu J, Epstein DL and Gonzalez P (2009) Alterations in microRNA expression in stress-induced cellular senescence. Mech Ageing Dev 130, 731-741
  72. Sokolova V, Fiorino A, Zoni E et al (2015) The Effects of miR-20a on p21: Two Mechanisms Blocking Growth Arrest in TGF-beta-Responsive Colon Carcinoma. J Cell Physiol 230, 3105-3114
  73. Overhoff MG, Garbe JC, Koh J, Stampfer MR, Beach DH and Bishop CL (2014) Cellular senescence mediated by p16INK4A-coupled miRNA pathways. Nucleic Acids Res 42, 1606-1618
  74. Tome M, Sepulveda JC, Delgado M et al (2014) miR-335 correlates with senescence/aging in human mesenchymal stem cells and inhibits their therapeutic actions through inhibition of AP-1 activity. Stem Cells 32, 2229-2244
  75. Yu Y, Gao R, Kaul Z et al (2016) Loss-of-function screening to identify miRNAs involved in senescence: tumor suppressor activity of miRNA-335 and its new target CARF. Sci Rep 6, 30185
  76. Marasa BS, Srikantan S, Masuda K et al (2009) Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs. Sci Signal 2, ra69
  77. Martinez I, Cazalla D, Almstead LL, Steitz JA and DiMaio D (2011) miR-29 and miR-30 regulate B-Myb expression during cellular senescence. Proc Natl Acad Sci U S A 108, 522-527
  78. Zhou Z, Yin Y, Chang Q, Sun G, Lin J and Dai Y (2017) Downregulation of B-myb promotes senescence via the ROS-mediated p53/p21 pathway, in vascular endothelial cells. Cell Prolif 50, e12319
  79. Noonan EJ, Place RF, Basak S, Pookot D and Li LC (2010) miR-449a causes Rb-dependent cell cycle arrest and senescence in prostate cancer cells. Oncotarget 1, 349-358
  80. O'Loghlen A, Brookes S, Martin N, Rapisarda V, Peters G and Gil J (2015) CBX7 and miR-9 are part of an autoregulatory loop controlling p16(INK) (4a). Aging Cell 14, 1113-1121
  81. Dimri M, Carroll JD, Cho JH and Dimri GP (2013) microRNA-141 regulates BMI1 expression and induces senescence in human diploid fibroblasts. Cell Cycle 12, 3537-3546
  82. Venkataraman S, Alimova I, Fan R, Harris P, Foreman N and Vibhakar R (2010) MicroRNA 128a increases intracellular ROS level by targeting Bmi-1 and inhibits medulloblastoma cancer cell growth by promoting senescence. PLoS One 5, e10748
  83. Liang J, Zhang Y, Jiang G et al (2013) MiR-138 induces renal carcinoma cell senescence by targeting EZH2 and is downregulated in human clear cell renal cell carcinoma. Oncol Res 21, 83-91
  84. Philipot D, Guerit D, Platano D et al (2014) p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis Res Ther 16, R58
  85. Noguchi S, Mori T, Otsuka Y et al (2012) Anti-oncogenic microRNA-203 induces senescence by targeting E2F3 protein in human melanoma cells. J Biol Chem 287, 11769-11777
  86. Mudhasani R, Zhu Z, Hutvagner G et al (2008) Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells. J Cell Biol 181, 1055-1063
  87. Gomez-Cabello D, Adrados I, Gamarra D et al (2013) DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts. Aging Cell 12, 923-931
  88. Giglio S, Cirombella R, Amodeo R, Portaro L, Lavra L and Vecchione A (2013) MicroRNA miR-24 promotes cell proliferation by targeting the CDKs inhibitors p27Kip1 and p16INK4a. J Cell Physiol 228, 2015-2023