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Emerging Functions of microRNA-146a/b in Development and Breast Cancer

MicroRNA-146a/b in Development and Breast Cancer
  • Hanan S. Elsarraj
  • Shane R. Stecklein
  • Kelli Valdez
  • Fariba Behbod
Article

Abstract

MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression through translational repression or mRNA degradation. These molecules play critical roles in regulating normal developmental processes, but when deregulated, are causally linked to the pathogenesis of numerous diseases, including cancer. MicroRNA-146a and -146b are encoded by two different genes, but differ by only two bases and appear to function redundantly in many systems. Initial studies branded miR-146a/b as important mediators of inflammatory signaling, documenting the ability of these miRNAs to influence differentiation, proliferation, apoptosis and effector immune mechanisms within the hematopoietic system. Numerous contemporary studies now implicate miR-146a/b as pleiotropic regulators of tumorigenesis, as a polymorphism in miR-146a and altered expression of both miR-146a/b have been linked with cancer risk, tumor histogenesis and invasive and metastatic capacity in diverse cancers. Despite the numerous reports concerning miR-146a/b in human cancers, the mechanistic contributions of these miRNAs in both normal and neoplastic mammary gland development and biology remains poorly characterized.

Keywords

miRNA miR-146a miR-146b-5p Breast cancer rs2910164 Single nucleotide polymorphism (SNP) Mammary development Hormone regulation Hematopoiesis 

Abbreviations

MiRNAs

MicroRNAs

ncRNAs

Non-coding RNAs

AGO2

Argonaute 2

XPO5

Exportin 5

DBR1

Lariat debranching enzyme

TRBP

TAR RNA binding protein

RISC

RNA-induced silencing complex

LPS

Lipopolysaccharide

NFκB

Nuclear factor kappa-light-chain-enhancer of activated B cells

IRAK1

Interleukin (IL)-1 receptor associated kinase

TRAF6

TNF receptor-associated factor 6

AP-1

Activating protein-1

TLR

Toll-like receptors

MDS

Myelodysplastic syndrome

HSPCs

Hematopoietic stem/progenitor cells

HBEC

Human bronchial epithelial cells

SNP

Single-nucleotide polymorphism

ER

Estrogen receptor α

PR

Progesterone receptor

BRCA1/2

Breast cancer type 1/2 susceptibility protein

TGFβ

Transforming growth factor beta

STAT3

Signal transducer and activator of transcription 3

VSMC

Vascular smooth muscle cells

KLF4

Krüppel-like factor 4

EMT

Epithelial-mesenchymal transition

PTC

Papillary thyroid cancers

BRMS1

Breast cancer metastasis suppressor 1

BRAF

Serine/threonine-protein kinase B-Raf

GBM

Glioblastoma multiforme

ECM

Extracellular matrix

EGFR

Epidermal growth factor receptor

MMP16

Matrix metalloproteinase 16

MTA-2

Metastasis-associated protein 2

References

  1. 1.
    Alexander RP, Fang G, Rozowsky J, Snyder M, Gerstein MB. Annotating non-coding regions of the genome. Nat Rev Genet. 2010;11(8):559–71.CrossRefPubMedGoogle Scholar
  2. 2.
    Ohno S. So much “junk” DNA in our genome. Brookhaven Symp Biol. 1972;23:366–70.PubMedGoogle Scholar
  3. 3.
    He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–74.CrossRefPubMedGoogle Scholar
  5. 5.
    Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol. 2006;13(12):1097–101.CrossRefPubMedGoogle Scholar
  6. 6.
    Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004;23(20):4051–60.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425(6956):415–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC. The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell. 2007;130(1):89–100.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell. 2001;106(1):23–34.CrossRefPubMedGoogle Scholar
  10. 10.
    Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science. 2001;293(5531):834–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Ketting RF, Fischer SE, Bernstein E, Sijen T, Hannon GJ, Plasterk RH. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 2001;15(20):2654–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Knight SW, Bass BL. A role for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans. Science. 2001;293(5538):2269–71.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005;436(7051):740–4.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005;123(4):631–40.CrossRefPubMedGoogle Scholar
  15. 15.
    Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37(5):495–500.CrossRefPubMedGoogle Scholar
  16. 16.
    Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002;12(9):735–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Cai X, Lu S, Zhang Z, Gonzalez CM, Damania B, Cullen BR. Kaposi’s sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc Natl Acad Sci U S A. 2005;102(15):5570–5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet. 2005;37(7):766–70.CrossRefPubMedGoogle Scholar
  19. 19.
    Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell. 2003;115(7):787–98.CrossRefPubMedGoogle Scholar
  20. 20.
    Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103(33):12481–6.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med. 2011;208(6):1189–201.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hou J, Wang P, Lin L, Liu X, Ma F, An H, et al. MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol. 2009;183(3):2150–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Nahid MA, Pauley KM, Satoh M, Chan EK. miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY. J Biol Chem. 2009;284(50):34590–9.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lindsay MA. microRNAs and the immune response. Trends Immunol. 2008;29(7):343–51.CrossRefPubMedGoogle Scholar
  25. 25.
    Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2010;16(1):49–58.CrossRefPubMedGoogle Scholar
  26. 26.
    Labbaye C, Spinello I, Quaranta MT, Pelosi E, Pasquini L, Petrucci E, et al. A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis. Nat Cell Biol. 2008;10(7):788–801.CrossRefPubMedGoogle Scholar
  27. 27.
    Opalinska JB, Bersenev A, Zhang Z, Schmaier AA, Choi J, Yao Y, et al. MicroRNA expression in maturing murine megakaryocytes. Blood. 2010;116(23):e128–38.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Liu X, Nelson A, Wang X, Kanaji N, Kim M, Sato T, et al. MicroRNA-146a modulates human bronchial epithelial cell survival in response to the cytokine-induced apoptosis. Biochem Biophys Res Commun. 2009;380(1):177–82.CrossRefPubMedGoogle Scholar
  29. 29.
    Sun SG, Zheng B, Han M, Fang XM, Li HX, Miao SB, et al. miR-146a and Kruppel-like factor 4 form a feedback loop to participate in vascular smooth muscle cell proliferation. EMBO Rep. 2011;12(1):56–62.CrossRefPubMedGoogle Scholar
  30. 30.
    Hurst DR, Edmonds MD, Welch DR. Metastamir: the field of metastasis-regulatory microRNA is spreading. Cancer Res. 2009;69(19):7495–8.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yip L, Kelly L, Shuai Y, Armstrong MJ, Nikiforov YE, Carty SE, et al. MicroRNA signature distinguishes the degree of aggressiveness of papillary thyroid carcinoma. Ann Surg Oncol. 2011;18(7):2035–41.CrossRefPubMedGoogle Scholar
  32. 32.
    He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, et al. The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci U S A. 2005;102(52):19075–80.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Chou CK, Chen RF, Chou FF, Chang HW, Chen YJ, Lee YF, et al. miR-146b is highly expressed in adult papillary thyroid carcinomas with high risk features including extrathyroidal invasion and the BRAF(V600E) mutation. Thyroid. 2010;20(5):489–94.CrossRefPubMedGoogle Scholar
  34. 34.
    Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003;63(7):1454–7.PubMedGoogle Scholar
  35. 35.
    Xia H, Qi Y, Ng SS, Chen X, Li D, Chen S, et al. microRNA-146b inhibits glioma cell migration and invasion by targeting MMPs. Brain Res. 2009;1269:158–65.CrossRefPubMedGoogle Scholar
  36. 36.
    Katakowski M, Zheng X, Jiang F, Rogers T, Szalad A, Chopp M. MiR-146b-5p suppresses EGFR expression and reduces in vitro migration and invasion of glioma. Cancer Invest. 2010;28(10):1024–30.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sathornsumetee S, Rich JN. Designer therapies for glioblastoma multiforme. Ann N Y Acad Sci. 2008;1142:108–32.CrossRefPubMedGoogle Scholar
  38. 38.
    Mei J, Bachoo R, Zhang CL. MicroRNA-146a inhibits glioma development by targeting Notch1. Mol Cell Biol. 2011;31(17):3584–92.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Li Y, Vandenboom 2nd TG, Wang Z, Kong D, Ali S, Philip PA, et al. miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res. 2010;70(4):1486–95.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kogo R, Mimori K, Tanaka F, Komune S, Mori M. Clinical significance of miR-146a in gastric cancer cases. Clin Cancer Res. 2011;17(13):4277–84.CrossRefPubMedGoogle Scholar
  41. 41.
    Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A. Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci U S A. 2008;105(20):7269–74.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Jazdzewski K, Liyanarachchi S, Swierniak M, Pachucki J, Ringel MD, Jarzab B, et al. Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer. Proc Natl Acad Sci U S A. 2009;106(5):1502–5.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lee NP, Leung KW, Cheung N, Lam BY, Xu MZ, Sham PC, et al. Comparative proteomic analysis of mouse livers from embryo to adult reveals an association with progression of hepatocellular carcinoma. Proteomics. 2008;8(10):2136–49.CrossRefPubMedGoogle Scholar
  44. 44.
    Akkiz H, Bayram S, Bekar A, Akgollu E, Uskudar O, Sandikci M. No association of pre-microRNA-146a rs2910164 polymorphism and risk of hepatocellular carcinoma development in Turkish population: a case-control study. Gene. 2011;486(1–2):104–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Zeng Y, Sun QM, Liu NN, Dong GH, Chen J, Yang L, et al. Correlation between pre-miR-146a C/G polymorphism and gastric cancer risk in Chinese population. World J Gastroenterol. 2010;16(28):3578–83.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Okubo M, Tahara T, Shibata T, Yamashita H, Nakamura M, Yoshioka D, et al. Association between common genetic variants in pre-microRNAs and gastric cancer risk in Japanese population. Helicobacter. 2010;15(6):524–31.CrossRefPubMedGoogle Scholar
  47. 47.
    Guo H, Wang K, Xiong G, Hu H, Wang D, Xu X, et al. A functional varient in microRNA-146a is associated with risk of esophageal squamous cell carcinoma in Chinese Han. Fam Cancer. 2010;9(4):599–603.CrossRefPubMedGoogle Scholar
  48. 48.
    Xu B, Feng NH, Li PC, Tao J, Wu D, Zhang ZD, et al. A functional polymorphism in Pre-miR-146a gene is associated with prostate cancer risk and mature miR-146a expression in vivo. Prostate. 2010;70(5):467–72.PubMedGoogle Scholar
  49. 49.
    Yue C, Wang M, Ding B, Wang W, Fu S, Zhou D, et al. Polymorphism of the pre-miR-146a is associated with risk of cervical cancer in a Chinese population. Gynecol Oncol. 2011;122(1):33–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Zhou B, Wang K, Wang Y, Xi M, Zhang Z, Song Y, et al. Common genetic polymorphisms in pre-microRNAs and risk of cervical squamous cell carcinoma. Mol Carcinog. 2011;50(7):499–505.CrossRefPubMedGoogle Scholar
  51. 51.
    Vinci S, Gelmini S, Pratesi N, Conti S, Malentacchi F, Simi L, et al. Genetic variants in miR-146a, miR-149, miR-196a2, miR-499 and their influence on relative expression in lung cancers. Clin Chem Lab Med 2011.Google Scholar
  52. 52.
    Lin J, Horikawa Y, Tamboli P, Clague J, Wood CG, Wu X. Genetic variations in microRNA-related genes are associated with survival and recurrence in patients with renal cell carcinoma. Carcinogenesis. 2010;31(10):1805–12.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Permuth-Wey J, Thompson RC, Burton Nabors L, Olson JJ, Browning JE, Madden MH, et al. A functional polymorphism in the pre-miR-146a gene is associated with risk and prognosis in adult glioma. J Neurooncol. 2011;105(3):639–46.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Shen J, Ambrosone CB, DiCioccio RA, Odunsi K, Lele SB, Zhao H. A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis. Carcinogenesis. 2008;29(10):1963–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Pastrello C, Polesel J, Della Puppa L, Viel A, Maestro R. Association between hsa-mir-146a genotype and tumor age-of-onset in BRCA1/BRCA2-negative familial breast and ovarian cancer patients. Carcinogenesis. 2010;31(12):2124–6.CrossRefPubMedGoogle Scholar
  56. 56.
    Catucci I, Yang R, Verderio P, Pizzamiglio S, Heesen L, Hemminki K, et al. Evaluation of SNPs in miR-146a, miR196a2 and miR-499 as low-penetrance alleles in German and Italian familial breast cancer cases. Hum Mutat. 2010;31(1):E1052–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, et al. Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers. EMBO Mol Med. 2011;3(5):279–90.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Garcia AI, Cox DG, Barjhoux L, Verny-Pierre C, Barnes D, Antoniou AC, et al. The rs2910164:G > C SNP in the MIR146A gene is not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Hum Mutat 2011.Google Scholar
  59. 59.
    Gao LB, Bai P, Pan XM, Jia J, Li LJ, Liang WB, et al. The association between two polymorphisms in pre-miRNAs and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2011;125(2):571–4.CrossRefPubMedGoogle Scholar
  60. 60.
    Bockmeyer CL, Christgen M, Muller M, Fischer S, Ahrens P, Langer F, et al. MicroRNA profiles of healthy basal and luminal mammary epithelial cells are distinct and reflected in different breast cancer subtypes. Breast Cancer Res Treat. 2011;130(3):735–45.CrossRefPubMedGoogle Scholar
  61. 61.
    Kittrell FS, Carletti MZ, Kerbawy S, Heestand J, Xian W, Zhang M, et al. Prospective isolation and characterization of committed and multipotent progenitors from immortalized mouse mammary epithelial cells with morphogenic potential. Breast Cancer Res. 2011;13(2):R41.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Turner NC, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene. 2007;26(14):2126–32.Google Scholar
  63. 63.
    Turner NC, Reis-Filho JS. Basal-like breast cancer and the BRCA1 phenotype. Oncogene. 2006;25(43):5846–53.Google Scholar
  64. 64.
    Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Sethi G, Sung B, Aggarwal BB. Nuclear factor-kappaB activation: from bench to bedside. Exp Biol Med (Maywood). 2008;233(1):21–31.CrossRefGoogle Scholar
  66. 66.
    Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J, Benz CC. Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 2008;27(42):5643–7.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Hurst DR, Edmonds MD, Scott GK, Benz CC, Vaidya KS, Welch DR. Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis. Cancer Res. 2009;69(4):1279–83.CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Hanan S. Elsarraj
    • 1
  • Shane R. Stecklein
    • 1
  • Kelli Valdez
    • 1
  • Fariba Behbod
    • 1
  1. 1.Department of Pathology and Laboratory MedicineThe University of Kansas Medical CenterKansas CityUSA

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