MicroRNAs: Crucial Regulators of Stress

Author(s): Rabih Roufayel, Seifedine kadry*.

Journal Name: MicroRNA

Volume 9 , Issue 2 , 2020

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Graphical Abstract:


Background: Signaling pathways including gene silencing, cellular differentiation, homeostasis, development and apoptosis are regulated and controlled by a wide range of miRNAs.

Objective: Due to their potential binding sites in human-protein coding genes, many studies have also linked their altered expressions in various cancer types making them tumor suppressors agents.

Methods: Moreover, each miRNA is predicted to have many mRNA targets indicating their extensive regulatory role in cell survival and developmental processes. Nowadays, diagnosis of early cancer stage development is now dependent on variable miRNA expression levels as potential oncogenic biomarkers in validating and targeting microRNAs for cancer therapy.

Results: As the majority of miRNA, transcripts are derived from RNA polymerase II-directed transcription, stress response could result on a general reduction in the abundance of these transcripts. Over expression of various microRNAs have lead to B cell malignancy, potentiated KrasG12Dinduced lung tumorigenesis, chronic lymphocytic leukemia, lymphoproliferative disease and autoimmunity.

Conclusion: Altered miRNA expressions could have a significant impact on the abundance of proteins, making them attractive candidates as biomarkers for cancer detection and important regulators of apoptosis.

Keywords: Apoptosis, cancer, miRNAs, regulators, stress, leukemia.

Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 2015; 16(7): 421-33.
[http://dx.doi.org/10.1038/nrg3965] [PMID: 26077373]
Iyer MK, Niknafs YS, Malik R, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 2015; 47(3): 199-208.
[http://dx.doi.org/10.1038/ng.3192] [PMID: 25599403]
Consortium F. Finishing the euchromatic sequence of the human genome. Nature 2004; 431(7011): 931-45.
[http://dx.doi.org/10.1038/nature03001] [PMID: 15496913]
Frith MC, Pheasant M, Mattick JS. The amazing complexity of the human transcriptome. Eur J Hum Genet 2005; 13(8): 894-7.
[http://dx.doi.org/10.1038/sj.ejhg.5201459] [PMID: 15970949]
Lai EC, Burks C, Posakony JW. The K box, a conserved 3′ UTR sequence motif, negatively regulates accumulation of enhancer of split complex transcripts. Development 1998; 125(20): 4077-88.
[PMID: 9735368]
Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000; 403(6772): 901-6.
[http://dx.doi.org/10.1038/35002607] [PMID: 10706289]
Wang Y, Li Z, He C, et al. MicroRNAs expression signatures are associated with lineage and survival in acute leukemias. Blood Cells Mol Dis 2010; 44(3): 191-7.
[http://dx.doi.org/10.1016/j.bcmd.2009.12.010] [PMID: 20110180]
Flynt AS, Lai EC. Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nat Rev Genet 2008; 9(11): 831-42.
[http://dx.doi.org/10.1038/nrg2455] [PMID: 18852696]
Hammond SM. MicroRNA therapeutics: a new niche for antisense nucleic acids. Trends Mol Med 2006; 12(3): 99-101.
[http://dx.doi.org/10.1016/j.molmed.2006.01.004] [PMID: 16473043]
Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 2010; 79: 351-79.
[http://dx.doi.org/10.1146/annurev-biochem-060308-103103] [PMID: 20533884]
Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science 2001; 294(5543): 853-8.
[http://dx.doi.org/10.1126/science.1064921] [PMID: 11679670]
Lee Y, Kim M, Han J, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004; 23(20): 4051-60.
[http://dx.doi.org/10.1038/sj.emboj.7600385] [PMID: 15372072]
Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 2006; 13(12): 1097-101.
[http://dx.doi.org/10.1038/nsmb1167] [PMID: 17099701]
Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 2003; 17(24): 3011-6.
[http://dx.doi.org/10.1101/gad.1158803] [PMID: 14681208]
MacRae IJ, Ma E, Zhou M, Robinson CV, Doudna JA. In vitro reconstitution of the human RISC-loading complex. Proc Natl Acad Sci USA 2008; 105(2): 512-7.
[http://dx.doi.org/10.1073/pnas.0710869105] [PMID: 18178619]
Guo Y, Sun J, Lai D. Role of microRNAs in premature ovarian insufficiency. Reprod Biol Endocrinol 2017; 15(1): 38.
[http://dx.doi.org/10.1186/s12958-017-0256-3] [PMID: 28499456]
Zhang X, Zeng Y. Regulation of mammalian microRNA expression. J Cardiovasc Transl Res 2010; 3(3): 197-203.
[http://dx.doi.org/10.1007/s12265-010-9166-x] [PMID: 20560040]
Hu J, Zhai C, Hu J, et al. miR-23a inhibited IL-17-mediated proinflammatory mediators expression via targeting IKKα in articular chondrocytes. Int Immunopharmacol 2017; 43: 1-6.
[http://dx.doi.org/10.1016/j.intimp.2016.11.031] [PMID: 27936459]
Golan D, Levy C, Friedman B, Shomron N. Biased hosting of intronic microRNA genes. Bioinformatics 2010; 26(8): 992-5.
[http://dx.doi.org/10.1093/bioinformatics/btq077] [PMID: 20185406]
Feng Z, Zhang C, Wu R, Hu W. Tumor suppressor p53 meets microRNAs. J Mol Cell Biol 2011; 3(1): 44-50.
[http://dx.doi.org/10.1093/jmcb/mjq040] [PMID: 21278451]
Roufayel R, Johnston DS, Mosser DD. The elimination of miR-23a in heat-stressed cells promotes NOXA-induced cell death and is prevented by HSP70. Cell Death Dis 2014; 5e: 1546.
[http://dx.doi.org/10.1038/cddis.2014.484] [PMID: 25429623]
Han H, Qu G, Han C, et al. miR-34a, miR-21 and miR-23a as potential biomarkers for coronary artery disease: a pilot microarray study and confirmation in a 32 patient cohort. Exp Mol Med 2015; 47(2) e138
[http://dx.doi.org/10.1038/emm.2014.81] [PMID: 25656948]
Obernosterer G, Leuschner PJ, Alenius M, Martinez J. Post-transcriptional regulation of microRNA expression. RNA 2006; 12(7): 1161-7.
[http://dx.doi.org/10.1261/rna.2322506] [PMID: 16738409]
Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science 2008; 320(5872): 97-100.
[http://dx.doi.org/10.1126/science.1154040] [PMID: 18292307]
Guil S, Cáceres JF. The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat Struct Mol Biol 2007; 14(7): 591-6.
[http://dx.doi.org/10.1038/nsmb1250] [PMID: 17558416]
Zhu H, Shah S, Shyh-Chang N, et al. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat Genet 2010; 42(7): 626-30.
[http://dx.doi.org/10.1038/ng.593] [PMID: 20512147]
Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 2005; 102(39): 13944-9.
[http://dx.doi.org/10.1073/pnas.0506654102] [PMID: 16166262]
Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 2010; 9(10): 775-89.
[http://dx.doi.org/10.1038/nrd3179] [PMID: 20885409]
Friedman RC, Farh KKH, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19(1): 92-105.
[http://dx.doi.org/10.1101/gr.082701.108] [PMID: 18955434]
Krek A, Grün D, Poy MN, et al. Combinatorial microRNA target predictions. Nat Genet 2005; 37(5): 495-500.
[http://dx.doi.org/10.1038/ng1536] [PMID: 15806104]
Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 2007; 39(5): 673-7.
[http://dx.doi.org/10.1038/ng2003] [PMID: 17401365]
Wilmink GJ, Roth CL, Ibey BL, et al. Identification of microRNAs associated with hyperthermia-induced cellular stress response. Cell Stress Chaperones 2010; 15(6): 1027-38.
[http://dx.doi.org/10.1007/s12192-010-0189-7] [PMID: 20352393]
Iwasaki S, Kobayashi M, Yoda M, et al. Hsc70/Hsp90 chaperone machinery mediates ATP-dependent RISC loading of small RNA duplexes. Mol Cell 2010; 39(2): 292-9.
[http://dx.doi.org/10.1016/j.molcel.2010.05.015] [PMID: 20605501]
Bandi N, Zbinden S, Gugger M, et al. miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Res 2009; 69(13): 5553-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4277] [PMID: 19549910]
Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004; 64(11): 3753-6.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0637] [PMID: 15172979]
Mott JL, Kobayashi S, Bronk SF, Gores GJ. mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 2007; 26(42): 6133-40.
[http://dx.doi.org/10.1038/sj.onc.1210436] [PMID: 17404574]
Hayashita Y, Osada H, Tatematsu Y, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 2005; 65(21): 9628-32.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-2352] [PMID: 16266980]
Chang TC, Yu D, Lee YS, et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 2008; 40(1): 43-50.
[http://dx.doi.org/10.1038/ng.2007.30] [PMID: 18066065]
Kasinski AL, Slack FJ. Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer 2011; 11(12): 849-64.
[http://dx.doi.org/10.1038/nrc3166] [PMID: 22113163]
Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 2012; 4(3): 143-59.
[http://dx.doi.org/10.1002/emmm.201100209] [PMID: 22351564]
Lima RT, Busacca S, Almeida GM, Gaudino G, Fennell DA, Vasconcelos MH. MicroRNA regulation of core apoptosis pathways in cancer. Eur J Cancer 2011; 47(2): 163-74.
[http://dx.doi.org/10.1016/j.ejca.2010.11.005] [PMID: 21145728]
Chhabra R, Dubey R, Saini N. Cooperative and individualistic functions of the microRNAs in the miR-23a~27a~24-2 cluster and its implication in human diseases. Mol Cancer 2010; 9: 232.
[http://dx.doi.org/10.1186/1476-4598-9-232] [PMID: 20815877]
Chen Q, Xu J, Li L, et al. MicroRNA-23a/b and microRNA-27a/b suppress Apaf-1 protein and alleviate hypoxia-induced neuronal apoptosis. Cell Death Dis 2014; 5 e1132
[http://dx.doi.org/10.1038/cddis.2014.92] [PMID: 24651435]
Mao J, Lv Z, Zhuang Y. MicroRNA-23a is involved in tumor necrosis factor-α induced apoptosis in mesenchymal stem cells and myocardial infarction. Exp Mol Pathol 2014; 97(1): 23-30.
[http://dx.doi.org/10.1016/j.yexmp.2013.11.005] [PMID: 4269648]
Morey TM, Roufayel R, Johnston DS, Fletcher AS, Mosser DD. Heat shock inhibition of CDK5 increases NOXA levels through miR-23a repression. J Biol Chem 2015; 290(18): 11443-54.
[http://dx.doi.org/10.1074/jbc.M114.625988] [PMID: 25829494]
Hermeking H, Lengauer C, Polyak K, et al. 14-3-3sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1997; 1(1): 3-11.
[http://dx.doi.org/10.1016/S1097-2765(00)80002-7] [PMID: 9659898]
Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K. Modulation of microRNA processing by p53. Nature 2009; 460(7254): 529-33.
[http://dx.doi.org/10.1038/nature08199] [PMID: 19626115]
Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annu Rev Pathol 2014; 9: 287-314.
[http://dx.doi.org/10.1146/annurev-pathol-012513-104715] [PMID: 24079833]
Xia L, Zhang D, Du R, et al. miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer 2008; 123(2): 372-9.
[http://dx.doi.org/10.1002/ijc.23501] [PMID: 18449891]
Kojima K, Fujita Y, Nozawa Y, Deguchi T, Ito M. MiR-34a attenuates paclitaxel-resistance of hormone-refractory prostate cancer PC3 cells through direct and indirect mechanisms. Prostate 2010; 70(14): 1501-12.
[http://dx.doi.org/10.1002/pros.21185] [PMID: 20687223]
Zhang C, Zhang J, Zhang A, et al. PUMA is a novel target of miR-221/222 in human epithelial cancers. Int J Oncol 2010; 37(6): 1621-6.
[PMID: 21042732]
Ouyang YB, Xu L, Lu Y, et al. Astrocyte-enriched miR-29a targets PUMA and reduces neuronal vulnerability to forebrain ischemia. Glia 2013; 61(11): 1784-94.
[http://dx.doi.org/10.1002/glia.22556] [PMID: 24038396]
Veronese A, Lupini L, Consiglio J, et al. Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Res 2010; 70(8): 3140-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-4456] [PMID: 20388800]
Yin C, Wang X, Kukreja RC. Endogenous microRNAs induced by heat-shock reduce myocardial infarction following ischemia-reperfusion in mice. FEBS Lett 2008; 582(30): 4137-42.
[http://dx.doi.org/10.1016/j.febslet.2008.11.014] [PMID: 19041309]
Srivastava N, Manvati S, Srivastava A, et al. miR-24-2 controls H2AFX expression regardless of gene copy number alteration and induces apoptosis by targeting antiapoptotic gene BCL-2: a potential for therapeutic intervention. Breast Cancer Res 2011; 13(2): R39.
[http://dx.doi.org/10.1186/bcr2861] [PMID: 21463514]
Musto A, Navarra A, Vocca A, et al. miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis. Cell Death Differ 2015; 22(6): 1047-57.
[http://dx.doi.org/10.1038/cdd.2014.198] [PMID: 25476774]
Zhang L, Li J, Xu W. A review of the role of PUMA, Noxa and Bim in the tumorigenesis, therapy and drug resistance of chronic lymphocytic leukemia. Nature 2012; 1: 7.
[PMID: 23175245]
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350(21): 2129-39.
[http://dx.doi.org/10.1056/NEJMoa040938] [PMID: 15118073]
Ebert MS, Sharp PA. MicroRNA sponges: progress and possibilities. RNA 2010; 16(11): 2043-50.
[http://dx.doi.org/10.1261/rna.2414110] [PMID: 20855538]
Tsang JS, Ebert MS, van Oudenaarden A. Genome-wide dissection of microRNA functions and cotargeting networks using gene set signatures. Mol Cell 2010; 38(1): 140-53.
[http://dx.doi.org/10.1016/j.molcel.2010.03.007] [PMID: 20385095]
Choi WY, Giraldez AJ, Schier AF. Target protectors reveal dampening and balancing of nodal agonist and antagonist by miR-430. Science 2007; 318(5848): 271-4.
[http://dx.doi.org/10.1126/science.1147535] [PMID: 17761850]
Agostini M, Knight RA. miR-34: from bench to bedside. Oncotarget 2014; 5(4): 872-81.
Bouchie A. First microRNA mimic enters clinic. Nat Biotechnol 2013; 31(7): 577.
[http://dx.doi.org/10.1038/nbt0713-577] [PMID: 23839128]
Daige CL, Wiggins JF, Priddy L, Nelligan-Davis T, Zhao J, Brown D. Systemic delivery of a miR34a mimic as a potential therapeutic for liver cancer. Mol Cancer Ther 2014; 13(10): 2352-60.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0209] [PMID: 25053820]
Leung AK, Sharp PA. MicroRNA functions in stress responses. Mol Cell 2010; 40(2): 205-15.
[http://dx.doi.org/10.1016/j.molcel.2010.09.027] [PMID: 20965416]
Place RF, Noonan EJ. Non-coding RNAs turn up the heat: an emerging layer of novel regulators in the mammalian heat shock response. Cell Stress Chaperones 2014; 19(2): 159-72.
[http://dx.doi.org/10.1007/s12192-013-0456-5] [PMID: 24002685]
Liu X, Sempere LF, Ouyang H, et al. MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors. J Clin Invest 2010; 120(4): 1298-309.
[http://dx.doi.org/10.1172/JCI39566] [PMID: 20237410]
Oshlag JZ, Devasthanam AS, Tomasi TB. Mild hyperthermia enhances the expression and induces oscillations in the Dicer protein. Int J Hyperthermia 2013; 29(1): 51-61.
[http://dx.doi.org/10.3109/02656736.2012.753471] [PMID: 23311378]
Yu J, Liu F, Yin P, et al. Integrating miRNA and mRNA expression profiles in response to heat stress-induced injury in rat small intestine. Funct Integr Genomics 2011; 11(2): 203-13.
[http://dx.doi.org/10.1007/s10142-010-0198-8] [PMID: 21057845]

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Year: 2020
Page: [93 - 100]
Pages: 8
DOI: 10.2174/2211536608666190625120127

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