Human Aging and Cancer: Role of miRNA in Tumor Microenvironment

  • Oleta A. Sandiford
  • Caitlyn A. Moore
  • Jun Du
  • Mathieu Boulad
  • Marina Gergues
  • Hussam Eltouky
  • Pranela RameshwarEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1056)


Human aging is an inevitable and complex phenomenon characterized by a progressive, gradual degradation of physiological and cellular processes that leads from vulnerability to death. Mammalian somatic cells display limited proliferative properties in vitro that results in a process of permanent cell cycle arrest commonly known as senescence. Events leading to cellular senescence are complex but may be due to the increase in tumor suppressor genes, caused by lifetime somatic mutations. Cumulative mutation leaves an imprint on the genome of the cell, an important risk factor for the occurrence of cancer. Adults over the age of 65+ are vulnerable to age related diseases such as cancers but such changes may begin at middle age. MicroRNAs (miRNAs), which are small non-coding RNA, can regulate cancer progression, recurrence and metastasis. This chapter discusses the role of miRNA in tumor microenvironment, consequent to aging.


miRNA Breast cancer Aging Hematopoiesis Microenvironment Bone marrow 


  1. 1.
    Kamminga LM, de Haan G (2006) Cellular memory and hematopoietic stem cell aging. Stem Cells 24:1143–1149PubMedCrossRefGoogle Scholar
  2. 2.
    Montecino-Rodriguez E, Berent-Maoz B, Dorshkind K (2013) Causes, consequences, and reversal of immune system aging. J Clin Invest 123:958–965PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Dorshkind K (2010) Not a split decision for human hematopoiesis. Nat Immunol 11:569–570PubMedCrossRefGoogle Scholar
  4. 4.
    Ahima RS (2009) Connecting obesity, aging and diabetes. Nat Med 15:996–997PubMedCrossRefGoogle Scholar
  5. 5.
    Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621PubMedCrossRefGoogle Scholar
  6. 6.
    Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K et al (2006) Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol 8:1291–1297PubMedCrossRefGoogle Scholar
  8. 8.
    Mudhasani R, Zhu Z, Hutvagner G, Eischen CM, Lyle S, Hall LL et al (2008) Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells. J Cell Biol 181:1055–1063PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O et al (2005) Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 37:766–770PubMedCrossRefGoogle Scholar
  10. 10.
    Lim PK, Bliss SA, Patel SA, Taborga M, Dave MA, Gregory LA et al (2011) Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Res 71:1550–1560PubMedCrossRefGoogle Scholar
  11. 11.
    Chen X, Liang H, Zhang J, Zen K, Zhang CY (2012) Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol 22:125–132PubMedCrossRefGoogle Scholar
  12. 12.
    Ma X, Becker Buscaglia LE, Barker JR, Li Y (2011) MicroRNAs in NF-kappaB signaling. J Mol Cell Biol 3:159–166PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252PubMedCrossRefGoogle Scholar
  14. 14.
    Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4:11–22PubMedCrossRefGoogle Scholar
  15. 15.
    Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Goubran HA, Kotb RR, Stakiw J, Emara ME, Burnouf T (2014) Regulation of tumor growth and metastasis: the role of tumor microenvironment. Cancer Growth Metastasis 7:9–18PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Brucher BL, Jamall IS (2014) Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment. Cell Physiol Biochem 34:213–243PubMedCrossRefGoogle Scholar
  18. 18.
    Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM (2015) Exosome mediated communication within the tumor microenvironment. J Control Release 219:278–294PubMedCrossRefGoogle Scholar
  19. 19.
    Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM et al (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756–766PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Chan SH, Wang LH (2015) Regulation of cancer metastasis by microRNAs. J Biomed Sci 22:9PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Suzuki HI, Katsura A, Matsuyama H, Miyazono K (2015) MicroRNA regulons in tumor microenvironment. Oncogene 34:3085–3094PubMedCrossRefGoogle Scholar
  22. 22.
    Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647–658PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Si W, Li Y, Shao H, Hu R, Wang W, Zhang K et al (2016) MiR-34a inhibits breast cancer proliferation and progression by targeting Wnt1 in Wnt/beta-catenin signaling pathway. Am J Med Sci 352:191–199PubMedCrossRefGoogle Scholar
  24. 24.
    Iorio MV, Croce CM (2012) MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 4:143–159PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Li Q, Zhang D, Wang Y, Sun P, Hou X, Larner J et al (2013) MiR-21/Smad 7 signaling determines TGF-beta1-induced CAF formation. Sci Rep 3:2038PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Bullock MD, Pickard KM, Nielsen BS, Sayan AE, Jenei V, Mellone M et al (2013) Pleiotropic actions of miR-21 highlight the critical role of deregulated stromal microRNAs during colorectal cancer progression. Cell Death Dis 4:e684PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Kadera BE, Li L, Toste PA, Wu N, Adams C, Dawson DW et al (2013) MicroRNA-21 in pancreatic ductal adenocarcinoma tumor-associated fibroblasts promotes metastasis. PLoS One 8:e71978PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Wentz-Hunter KK, Potashkin JA (2011) The role of miRNAs as key regulators in the neoplastic microenvironment. Mol Biol Int 2011:839872PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ et al (2007) A microRNA signature of hypoxia. Mol Cell Biol 27:1859–1867PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Aprelikova O, Green JE (2012) MicroRNA regulation in cancer-associated fibroblasts. Cancer Immunol Immunother 61:231–237PubMedCrossRefGoogle Scholar
  31. 31.
    Zaravinos A (2015) The regulatory role of MicroRNAs in EMT and cancer. J Oncol 2015:865816PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Han M, Liu M, Wang Y, Chen X, Xu J, Sun Y et al (2012) Antagonism of miR-21 reverses epithelial-mesenchymal transition and cancer stem cell phenotype through AKT/ERK1/2 inactivation by targeting PTEN. PLoS One 7:e39520PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Esposito M, Kang Y (2014) Targeting tumor-stromal interactions in bone metastasis. Pharmacol Ther 141:222–233PubMedCrossRefGoogle Scholar
  34. 34.
    Kelly T, Suva LJ, Huang Y, MacLeod V, Miao H-Q, Walker RC et al (2005) Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer Res 65:5778–5784PubMedCrossRefGoogle Scholar
  35. 35.
    Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisted. Nat Rev Cancer 3:453–458CrossRefPubMedGoogle Scholar
  37. 37.
    Walker ND, Patel J, Munoz JL, Hu M, Guiro K, Sinha G et al (2016) The bone marrow niche in support of breast cancer dormancy. Cancer Lett 380:263–271PubMedCrossRefGoogle Scholar
  38. 38.
    Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes C et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802PubMedCrossRefGoogle Scholar
  39. 39.
    Agas D, Marchetti L, Douni E, Sabbieti MG (2015) The unbearable lightness of bone marrow homeostasis. Cytokine Growth Factor Rev 26:347–359PubMedCrossRefGoogle Scholar
  40. 40.
    Dhawan A, von Bonin M, Bray LJ, Freudenberg U, Pishali Bejestani E, Werner C et al (2016) Functional interference in the bone marrow microenvironment by disseminated breast cancer cells. Stem Cells 34:2224–2235PubMedCrossRefGoogle Scholar
  41. 41.
    Moharita AL, Taborga M, Corcoran KE, Bryan M, Patel PS, Rameshwar P (2006) SDF-1alpha regulation in breast cancer cells contacting bone marrow stroma is critical for normal hematopoiesis. Blood 108:3245–3252PubMedCrossRefGoogle Scholar
  42. 42.
    Patel SA, Ramkissoon SH, Bryan M, Pliner LF, Dontu G, Patel PS et al (2012) Delineation of breast cancer cell hierarchy identifies the subset responsible for dormancy. Sci Rep 2:906PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Habeck M (2000) Bone-marrow analysis predicts breast-cancer recurrence. Mol Med Today 6:256–257PubMedCrossRefGoogle Scholar
  44. 44.
    Braun S, Pantel K, Müller P, Janni W, Hepp F, Kentenich CRM et al (2000) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342:525–533PubMedCrossRefGoogle Scholar
  45. 45.
    Mansi JL, McDonnell T, Pople A, Rayter Z, Gazet JC, Coombes RC (1989) The fate of bone marrow micrometastases in patients with primary breast cancer. Clin Oncol 7:445–449CrossRefGoogle Scholar
  46. 46.
    Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celia-Terrassa T et al (2011) Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med 17:1101–1108PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Park SM, Gaur AB, Lengyel E, Peter ME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Gibbons DL, Lin W, Creighton CJ, Rizvi ZH, Gregory PA, Goodall GJ et al (2009) Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes Dev 23:2140–2151PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C et al (2013) MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154:311–324PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Lipton A, Cook R, Brown J, Body JJ, Smith M, Coleman R (2013) Skeletal-related events and clinical outcomes in patients with bone metastases and normal levels of osteolysis: exploratory analyses. Clin Oncol 25:217–226CrossRefGoogle Scholar
  51. 51.
    Gobel A, Browne AJ, Thiele S, Rauner M, Hofbauer LC, Rachner TD (2015) Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins. Breast Cancer Res Treat 154:623–631PubMedCrossRefGoogle Scholar
  52. 52.
    Yamaguchi M, Vikulina T, Weitzmann MN (2015) Gentian violet inhibits MDA-MB-231 human breast cancer cell proliferation, and reverses the stimulation of osteoclastogenesis and suppression of osteoblast activity induced by cancer cells. Oncol Rep 34:2156–2162PubMedCrossRefGoogle Scholar
  53. 53.
    Wang L, Wang J (2012) MicroRNA-mediated breast cancer metastasis: from primary site to distant organs. Oncogene 31:2499–2511PubMedCrossRefGoogle Scholar
  54. 54.
    Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2:584–593PubMedCrossRefGoogle Scholar
  55. 55.
    Asada N, Takeishi S, Frenette PS (2017) Complexity of bone marrow hematopoietic stem cell niche. Int J Hematol 106(1):45–54PubMedCrossRefGoogle Scholar
  56. 56.
    Gulei D, Mehterov N, Ling H, Stanta G, Braicu C, Berindan-Neagoe I (2017) The “good-cop bad-cop” TGF-beta role in breast cancer modulated by non-coding RNAs. Biochim Biophys Acta 1861:1661–1675PubMedCrossRefGoogle Scholar
  57. 57.
    Wang Y, Yu Y, Tsuyada A, Ren X, Wu X, Stubblefield K et al (2011) Transforming growth factor-beta regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM. Oncogene 30:1470–1480PubMedCrossRefGoogle Scholar
  58. 58.
    Jing D, Hao J, Shen Y, Tang G, Li ML, Huang SH et al (2015) The role of microRNAs in bone remodeling. Int J Oral Sci 7:131–143PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Aguirre-Ghiso JA (2007) Models, mechanisms, and clinical evidence for cancer dormancy. Nat Rev Cancer 7:834–846PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Abdullah LN, Chow EK-H (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Trans Med 2:3CrossRefGoogle Scholar
  61. 61.
    Bliss SA, Sinha G, Sandiford OA, Williams LM, Engelberth DJ, Guiro K et al (2016) Mesenchymal stem cell-derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res 76:5832–5844PubMedCrossRefGoogle Scholar
  62. 62.
    Ono M, Nobuyoshi K, Tominaga N, Yoshioka Y, Takeshita F, Takahashi R et al (2014) Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal 7(332):ra63PubMedCrossRefGoogle Scholar
  63. 63.
    Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111CrossRefGoogle Scholar
  64. 64.
    Velasco-Velazquez MA, Homsi N, De La Fuente M, Pestell RG (2012) Breast cancer stem cells. Int J Biochem Cell Biol 44:573–577PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10(2):R25PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Zhao J (2016) Cancer stem cells and chemoresistance: the smartest survives the raid. Pharmacol Ther 160:145–158PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C et al (2007) Let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123PubMedCrossRefGoogle Scholar
  68. 68.
    Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D et al (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138:592–603PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Gilkes DM (2016) Implications of hypoxia in breast cancer metastasis to bone. Int J Mol Sci 17(10):1669PubMedCentralCrossRefGoogle Scholar
  70. 70.
    Gilkes DM, Semenza GL (2013) Role of hypoxia-inducible factors in breast cancer metastasis. Future Oncol 9:1623–1636PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Mimeault M, Batra SK (2013) Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J Cell Mol Med 17:30–54PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Pakravan K, Babashah S, Sadeghizadeh M, Mowla SJ, Mossahebi-Mohammadi M, Ataei F et al (2017) MicroRNA-100 shuttled by mesenchymal stem cell-derived exosomes suppresses in vitro angiogenesis through modulating the mTOR/HIF-1alpha/VEGF signaling axis in breast cancer cells. Cell Oncol 40(5):457–470CrossRefGoogle Scholar
  73. 73.
    Galanis A, Pappa A, Giannakakis A, Lanitis E, Dangaj D, Sandaltzopoulos R (2008) Reactive oxygen species and HIF-1 signalling in cancer. Cancer Lett 266:12–20PubMedCrossRefGoogle Scholar
  74. 74.
    Costales MG, Haga CL, Velagapudi SP, Childs-Disney JL, Phinney DG, Disney MD (2017) Small molecule inhibition of microRNA-210 reprograms an oncogenic hypoxic circuit. J Am Chem Soc 139:3446–3455PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Bandara V, Michael MZ, Gleadle JM (2014) Hypoxia represses microRNA biogenesis proteins in breast cancer cells. BMC Cancer 14:533PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    King HW, Michael MZ, Gleadle JM (2012) Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 12:421PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Han M, Wang Y, Liu M, Bi X, Bao J, Zeng N et al (2012) MiR-21 regulates epithelial-mesenchymal transition phenotype and hypoxia-inducible factor-1alpha expression in third-sphere forming breast cancer stem cell-like cells. Cancer Sci 103:1058–1064PubMedCrossRefGoogle Scholar
  78. 78.
    Cha ST, Chen PS, Johansson G, Chu CY, Wang MY, Jeng YM et al (2010) MicroRNA-519c suppresses hypoxia-inducible factor-1alpha expression and tumor angiogenesis. Cancer Res 70:2675–2685PubMedCrossRefGoogle Scholar
  79. 79.
    Ivan M, Harris AL, Martelli F, Kulshreshtha R (2008) Hypoxia response and microRNAs: no longer two separate worlds. J Cell Mol Med 12:1426–1431PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Christopher AF, Kaur RP, Kaur G, Kaur A, Gupta V, Bansal P (2016) MicroRNA therapeutics: Discovering novel targets and developing specific therapy. Perspect Clin Res 7:68–74PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Czech M (2006) MicroRNAs as therapeutic targets. N Engl J Med 354:1194–1195PubMedCrossRefGoogle Scholar
  82. 82.
    Bader AG, Brown D, Winkler M (2010) The promise of microRNA replacement therapy. Cancer Res 70:7027–7030PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Jopling C, Yi M, Lancaster A, Lemon S, Sarnow P (2005) Modulation of hepatitis C virus RNA abundance by a liver-speci c MicroRNA. Science 309:1577–1581PubMedCrossRefGoogle Scholar
  84. 84.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838PubMedCrossRefGoogle Scholar
  85. 85.
    Zagryazhskaya A, Zhivotovsky B (2014) miRNAs in lung cancer: a link to aging. Ageing Res Rev 17:54–67PubMedCrossRefGoogle Scholar
  86. 86.
    Lee J, Hong J, Bonner D, Poon Z, Hammond P (2012) Self-assembled RNA interference microsponges for e cient siRNA delivery. Nat Mater 11:316–322PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Aravalli RN (2013) Development of MicroRNA therapeutics for hepatocellular carcinoma. Diagnostics (Basel) 3:170–191CrossRefGoogle Scholar
  88. 88.
    Bader A (2012) miR-34—A microRNA replacement therapy is headed to the clinic. Front Genet 3:120PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Ding G, Peng Z, Shang J, Kang Y, Ning H, Mao C (2017) LincRNA-p21 inhibits invasion and metastasis of hepatocellular carcinoma through miR-9/E-cadherin cascade signaling pathway molecular mechanism. Onco Targets Ther 10:3241–3247PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Zhou B, Xu H, Xia M, Sun C, Li N, Guo E et al (2017) Overexpressed miR-9 promotes tumor metastasis via targeting E-cadherin in serous ovarian cancer. Front Med 11:214–222PubMedCrossRefGoogle Scholar
  91. 91.
    Liu R, Liu C, Chen D, Yang WH, Liu X, Liu CG et al (2015) FOXP3 controls an miR-146/NF-kappaB negative feedback loop that inhibits apoptosis in breast cancer cells. Cancer Res 75:1703–1713PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci 102:13944–13949PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269PubMedCrossRefGoogle Scholar
  94. 94.
    Ouchida M, Kanzaki H, Ito S, Hanafusa H, Jitsumori Y, Tamaru S et al (2012) Novel direct targets of miR-19a identified in breast cancer cells by a quantitative proteomic approach. PLoS One 7:e44095PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283:1026–1033PubMedCrossRefGoogle Scholar
  96. 96.
    Xia H, Ooi LL, Hui KM (2012) MiR-214 targets beta-catenin pathway to suppress invasion, stem-like traits and recurrence of human hepatocellular carcinoma. PLoS One 7:e44206PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Nyholm AM, Lerche CM, Manfe V, Biskup E, Johansen P, Morling N et al (2014) miR-125b induces cellular senescence in malignant melanoma. BMC Dermatol 14:8PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Hou Z, Yin H, Chen C, Dai X, Li X, Liu B et al (2012) microRNA-146a targets the L1 cell adhesion molecule and suppresses the metastatic potential of gastric cancer. Mol Med Rep 6:501–506PubMedCrossRefGoogle Scholar
  99. 99.
    Kroesen BJ, Teteloshvili N, Smigielska-Czepiel K, Brouwer E, Boots AM, van den Berg A et al (2015) Immuno-miRs: critical regulators of T-cell development, function and ageing. Immunology 144:1–10PubMedCrossRefGoogle Scholar
  100. 100.
    Zhu ZJ, Huang P, Chong YX, Kang LX, Huang X, Zhu ZX et al (2016) MicroRNA-181a promotes proliferation and inhibits apoptosis by suppressing CFIm25 in osteosarcoma. Mol Med Rep 14:4271–4278PubMedCrossRefGoogle Scholar
  101. 101.
    Pan Y, Li J, Zhang Y, Wang N, Liang H, Liu Y et al (2016) Slug-upregulated miR-221 promotes breast cancer progression through suppressing E-cadherin expression. Sci Rep 6:25798PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Lambertini E, Lolli A, Vezzali F, Penolazzi L, Gambari R, Piva R (2012) Correlation between Slug transcription factor and miR-221 in MDA-MB-231 breast cancer cells. BMC Cancer 12:445PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Goldberger N, Walker RC, Kim CH, Winter S, Hunter KW (2013) Inherited variation in miR-290 expression suppresses breast cancer progression by targeting the metastasis susceptibility gene Arid4b. Cancer Res 73:2671–2681PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Hayes EL, Lewis-Wambi JS (2015) Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA. Breast Cancer Res 17:40PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Guo R, Abdelmohsen K, Morin PJ, Gorospe M (2013) Novel MicroRNA reporter uncovers repression of Let-7 by GSK-3beta. PLoS One 8:e66330PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Steiner DF, Thomas MF, JK H, Yang Z, Babiarz JE, Allen CD et al (2011) MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells. Immunity 35:169–181PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Feng C, Bai M, NZ Y, Wang XJ, Liu Z (2017) MicroRNA-181b negatively regulates the proliferation of human epidermal keratinocytes in psoriasis through targeting TLR4. J Cell Mol Med 21:278–285PubMedCrossRefGoogle Scholar
  108. 108.
    Zhang Y, Yang P, Sun T, Li D, Xu X, Rui Y et al (2013) miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol 15:284–294PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, Merck E et al (2013) MicroRNA-155 is required for effector CD8+ T cell responses to virus infection and cancer. Immunity 38:742–753PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Ling N, Gu J, Lei Z, Li M, Zhao J, Zhang HT et al (2013) microRNA-155 regulates cell proliferation and invasion by targeting FOXO3a in glioma. Oncol Rep 30:2111–2118PubMedCrossRefGoogle Scholar
  111. 111.
    Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155 inhibits IFN-gamma signaling in CD4+ T cells. Eur J Immunol 40:225–231PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR et al (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608–611PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Bischof O, Martinez-Zamudio RI (2015) MicroRNAs and lncRNAs in senescence: a review. IUBMB Life 67:255–267PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Verghese ET, Drury R, Green CA, Holliday DL, Lu X, Nash C et al (2013) MiR-26b is down-regulated in carcinoma-associated fibroblasts from ER-positive breast cancers leading to enhanced cell migration and invasion. J Pathol 231:388–399PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Ma YL, Zhang P, Wang F, Moyer MP, Yang JJ, Liu ZH et al (2011) Human embryonic stem cells and metastatic colorectal cancer cells shared the common endogenous human microRNA-26b. J Cell Mol Med 15:1941–1954PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Tekirdag KA, Korkmaz G, Ozturk DG, Agami R, Gozuacik D (2013) MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5. Autophagy 9:374–385PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Wang H, Flach H, Onizawa M, Wei L, McManus MT, Weiss A (2014) Negative regulation of Hif1a expression and TH17 differentiation by the hypoxia-regulated microRNA miR-210. Nat Immunol 15:393–401PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S et al (2009) MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol 10:1252–1259PubMedCrossRefGoogle Scholar
  119. 119.
    Wei S, Li Q, Li Z, Wang L, Zhang L, Xu Z (2016) miR-424-5p promotes proliferation of gastric cancer by targeting Smad3 through TGF-beta signaling pathway. Oncotarget 7:75185–75196PubMedPubMedCentralGoogle Scholar
  120. 120.
    Marasa BS, Srikantan S, Martindale JL, Kim MM, Lee EK, Gorospe M et al (2010) MicroRNA profiling in human diploid fibroblasts uncovers miR-519 role in replicative senescence. Aging 2:333–343PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Oleta A. Sandiford
    • 1
  • Caitlyn A. Moore
    • 1
  • Jun Du
    • 1
  • Mathieu Boulad
    • 1
  • Marina Gergues
    • 1
  • Hussam Eltouky
    • 1
  • Pranela Rameshwar
    • 1
    Email author
  1. 1.Division of Hematology/Oncology, Department of MedicineNew Jersey Medical School, Rutgers School of Biomedical Health ScienceNewarkUSA

Personalised recommendations