miRNAs are small regulatory RNAs that, due to their considerable potential to target a wide range of mRNAs, are implicated in essentially all biological process, including cancer. miR-10a is particularly interesting considering its conserved location in the Hox cluster of developmental regulators. A role for this microRNA has been described in developmental regulation as well as for various cancers. However, previous miR-10a studies are exclusively based on transient knockdowns of this miRNA and to extensively study miR-10a loss we have generated a miR-10a knock out mouse. Here we show that, in the Apcmin mouse model of intestinal neoplasia, female miR-10a deficient mice develop significantly more adenomas than miR-10+/+ and male controls. We further found that Lpo is extensively upregulated in the intestinal epithelium of mice deprived of miR-10a. Using in vitro assays, we demonstrate that the primary miR-10a target KLF4 can upregulate transcription of Lpo, whereas siRNA knockdown of KLF4 reduces LPO levels in HCT-116 cells. Furthermore, Klf4 is upregulated in the intestines of miR-10a knockout mice. Lpo has previously been shown to have the capacity to oxidize estrogens into potent depurinating mutagens, creating an instable genomic environment that can cause initiation of cancer. Therefore, we postulate that Lpo upregulation in the intestinal epithelium of miR-10a deficient mice together with the predominant abundance of estrogens in female animals mainly accounts for the sex-related cancer phenotype we observed. This suggests that miR-10a could be used as a potent diagnostic marker for discovering groups of women that are at high risk of developing colorectal carcinoma, which today is one of the leading causes of cancer-related deaths.
Vyšlo v časopise: Loss of miR-10a Activates and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice. PLoS Genet 9(10): e32767. doi:10.1371/journal.pgen.1003913 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003913
1. MitchellPS, ParkinRK, KrohEM, FritzBR, WymanSK, et al. (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105 : 10513–10518.
2. ParanjapeT, SlackFJ, WeidhaasJB (2009) MicroRNAs: tools for cancer diagnostics. Gut 58 : 1546–1554.
3. DengS, CalinGA, CroceCM, CoukosG, ZhangL (2008) Mechanisms of microRNA deregulation in human cancer. Cell Cycle 7 : 2643–2646.
4. TehlerD, Hoyland-KroghsboNM, LundAH (2011) The miR-10 microRNA precursor family. RNA Biol 8 : 728–734.
5. LundAH (2010) miR-10 in development and cancer. Cell Death Differ 17 : 209–214.
6. MansfieldJH, HarfeBD, NissenR, ObenauerJ, SrineelJ, et al. (2004) MicroRNA-responsive ‘sensor’ transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression. Nat Genet 36 : 1079–1083.
7. WolteringJM, DurstonAJ (2008) MiR-10 represses HoxB1a and HoxB3a in zebrafish. PLoS One 3: e1396.
8. GarzonR, PichiorriF, PalumboT, IulianoR, CimminoA, et al. (2006) MicroRNA fingerprints during human megakaryocytopoiesis. Proc Natl Acad Sci U S A 103 : 5078–5083.
9. HanL, WitmerPD, CaseyE, ValleD, SukumarS (2007) DNA methylation regulates MicroRNA expression. Cancer Biol Ther 6 : 1284–1288.
10. MaL, Teruya-FeldsteinJ, WeinbergRA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449 : 682–688.
11. GrimsonA, FarhKK, JohnstonWK, Garrett-EngeleP, LimLP, et al. (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27 : 91–105.
12. BartelDP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136 : 215–233.
13. AgirreX, Jimenez-VelascoA, San Jose-EnerizE, GarateL, BandresE, et al. (2008) Down-regulation of hsa-miR-10a in chronic myeloid leukemia CD34+ cells increases USF2-mediated cell growth. Mol Cancer Res 6 : 1830–1840.
14. WeissFU, MarquesIJ, WolteringJM, VleckenDH, AghdassiA, et al. (2009) Retinoic acid receptor antagonists inhibit miR-10a expression and block metastatic behavior of pancreatic cancer. Gastroenterology 137 : 2136–2137, 2136-2145, e2131-2137.
15. MoriartyCH, PursellB, MercurioAM (2010) miR-10b targets Tiam1: implications for Rac activation and carcinoma migration. J Biol Chem 285 : 20541–20546.
16. ChaiG, LiuN, MaJ, LiH, OblingerJL, et al. (2010) MicroRNA-10b regulates tumorigenesis in neurofibromatosis type 1. Cancer Sci 101 : 1997–2004.
17. JemalA, BrayF, CenterMM, FerlayJ, WardE, et al. (2011) Global cancer statistics. CA Cancer J Clin 61 : 69–90.
18. van den BrinkGR, OfferhausGJ (2007) The morphogenetic code and colon cancer development. Cancer Cell 11 : 109–117.
19. KinzlerKW, NilbertMC, SuLK, VogelsteinB, BryanTM, et al. (1991) Identification of FAP locus genes from chromosome 5q21. Science 253 : 661–665.
20. MiyoshiY, NagaseH, AndoH, HoriiA, IchiiS, et al. (1992) Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1 : 229–233.
21. NishishoI, NakamuraY, MiyoshiY, MikiY, AndoH, et al. (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253 : 665–669.
22. MarkowitzSD, BertagnolliMM (2009) Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 361 : 2449–2460.
23. MarkowitzSD, DawsonDM, WillisJ, WillsonJK (2002) Focus on colon cancer. Cancer Cell 1 : 233–236.
24. MonzoM, NavarroA, BandresE, ArtellsR, MorenoI, et al. (2008) Overlapping expression of microRNAs in human embryonic colon and colorectal cancer. Cell Res 18 : 823–833.
25. VoliniaS, CalinGA, LiuCG, AmbsS, CimminoA, et al. (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A 103 : 2257–2261.
26. SchwenkF, BaronU, RajewskyK (1995) A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res 23 : 5080–5081.
27. MoserAR, PitotHC, DoveWF (1990) A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247 : 322–324.
28. SuLK, KinzlerKW, VogelsteinB, PreisingerAC, MoserAR, et al. (1992) Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256 : 668–670.
29. GouldKA, DietrichWF, BorensteinN, LanderES, DoveWF (1996) Mom1 is a semi-dominant modifier of intestinal adenoma size and multiplicity in Min/+ mice. Genetics 144 : 1769–1776.
30. CormierRT, HongKH, HalbergRB, HawkinsTL, RichardsonP, et al. (1997) Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nat Genet 17 : 88–91.
31. SilvermanKA, KoratkarR, SiracusaLD, BuchbergAM (2002) Identification of the modifier of Min 2 (Mom2) locus, a new mutation that influences Apc-induced intestinal neoplasia. Genome Res 12 : 88–97.
32. BaranAA, SilvermanKA, ZeskandJ, KoratkarR, PalmerA, et al. (2007) The modifier of Min 2 (Mom2) locus: embryonic lethality of a mutation in the Atp5a1 gene suggests a novel mechanism of polyp suppression. Genome Res 17 : 566–576.
33. HurstingSD, SlagaTJ, FischerSM, DiGiovanniJ, PhangJM (1999) Mechanism-based cancer prevention approaches: targets, examples, and the use of transgenic mice. J Natl Cancer Inst 91 : 215–225.
34. HatziapostolouM, IliopoulosD (2011) Epigenetic aberrations during oncogenesis. Cell Mol Life Sci 68 : 1681–1702.
35. FilipowiczW, BhattacharyyaSN, SonenbergN (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9 : 102–114.
36. HuntzingerE, IzaurraldeE (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12 : 99–110.
37. FrankelLB, ChristoffersenNR, JacobsenA, LindowM, KroghA, et al. (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283 : 1026–1033.
38. WilsonPA, PlucinskiM (2011) A simple Bayesian estimate of direct RNAi gene regulation events from differential gene expression profiles. BMC Genomics 12 : 250.
39. SelbachM, SchwanhausserB, ThierfelderN, FangZ, KhaninR, et al. (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455 : 58–63.
40. BaekD, VillenJ, ShinC, CamargoFD, GygiSP, et al. (2008) The impact of microRNAs on protein output. Nature 455 : 64–71.
41. IhalinR, LoimarantaV, TenovuoJ (2006) Origin, structure, and biological activities of peroxidases in human saliva. Arch Biochem Biophys 445 : 261–268.
42. HamonCB, KlebanoffSJ (1973) A peroxidase-mediated, streptococcus mitis-dependent antimicrobial system in saliva. J Exp Med 137 : 438–450.
43. JosephyPD (1996) The role of peroxidase-catalyzed activation of aromatic amines in breast cancer. Mutagenesis 11 : 3–7.
44. CavalieriEL, StackDE, DevanesanPD, TodorovicR, DwivedyI, et al. (1997) Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci U S A 94 : 10937–10942.
45. Gorlewska-RobertsKM, TeitelCH, LayJOJr, RobertsDW, KadlubarFF (2004) Lactoperoxidase-catalyzed activation of carcinogenic aromatic and heterocyclic amines. Chem Res Toxicol 17 : 1659–1666.
46. BoltonJL, ThatcherGR (2008) Potential mechanisms of estrogen quinone carcinogenesis. Chem Res Toxicol 21 : 93–101.
47. CavalieriE, ChakravartiD, GuttenplanJ, HartE, IngleJ, et al. (2006) Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta 1766 : 63–78.
48. GradyWM, CarethersJM (2008) Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135 : 1079–1099.
49. LewisBP, BurgeCB, BartelDP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120 : 15–20.
50. BryantA, PalmaCA, JayaswalV, YangYW, LutherborrowM, et al. (2012) miR-10a is aberrantly overexpressed in Nucleophosmin1 mutated acute myeloid leukaemia and its suppression induces cell death. Mol Cancer 11 : 8.
51. McConnellBB, GhalebAM, NandanMO, YangVW (2007) The diverse functions of Kruppel-like factors 4 and 5 in epithelial biology and pathobiology. Bioessays 29 : 549–557.
52. HuR, ZuoY, ZuoL, LiuC, ZhangS, et al. (2011) KLF4 Expression Correlates with the Degree of Differentiation in Colorectal Cancer. Gut Liver 5 : 154–159.
53. HornsteinE, ShomronN (2006) Canalization of development by microRNAs. Nat Genet 38 Suppl: S20–24.
54. MiskaEA, Alvarez-SaavedraE, AbbottAL, LauNC, HellmanAB, et al. (2007) Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet 3: e215.
55. MendellJT, OlsonEN (2012) MicroRNAs in stress signaling and human disease. Cell 148 : 1172–1187.
56. ReiterB, MarshallVM, PhilipsSM (1980) The antibiotic activity of the lactoperoxidase-thiocyanate-hydrogen peroxide system in the calf abomasum. Res Vet Sci 28 : 116–122.
57. GotheforsL, MarklundS (1975) Lactoperoxidase activity in human milk and in saliva of newborn infants. Infect Immun 11 : 1210–1215.
58. LeighJA, FieldTR, WilliamsMR (1990) Two strains of Streptococcus uberis, of differing ability to cause clinical mastitis, differ in their ability to resist some host defence factors. Res Vet Sci 49 : 85–87.
59. KimBW, EsworthyRS, HahnMA, PfeiferGP, ChuFF (2012) Expression of lactoperoxidase in differentiated mouse colon epithelial cells. Free Radic Biol Med 52 : 1569–1576.
60. FurtmullerPG, JantschkoW, RegelsbergerG, JakopitschC, ArnholdJ, et al. (2002) Reaction of lactoperoxidase compound I with halides and thiocyanate. Biochemistry 41 : 11895–11900.
61. LiKM, TodorovicR, DevanesanP, HigginbothamS, KofelerH, et al. (2004) Metabolism and DNA binding studies of 4-hydroxyestradiol and estradiol-3,4-quinone in vitro and in female ACI rat mammary gland in vivo. Carcinogenesis 25 : 289–297.
62. ZahidM, KohliE, SaeedM, RoganE, CavalieriE (2006) The greater reactivity of estradiol-3,4-quinone vs estradiol-2,3-quinone with DNA in the formation of depurinating adducts: implications for tumor-initiating activity. Chem Res Toxicol 19 : 164–172.
63. SaeedM, RoganE, CavalieriE (2009) Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: the defining link to natural estrogens. Int J Cancer 124 : 1276–1284.
64. FernandezSV, RussoIH, RussoJ (2006) Estradiol and its metabolites 4-hydroxyestradiol and 2-hydroxyestradiol induce mutations in human breast epithelial cells. Int J Cancer 118 : 1862–1868.
65. LuoG, SantoroIM, McDanielLD, NishijimaI, MillsM, et al. (2000) Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nat Genet 26 : 424–429.
66. RudolphKL, MillardM, BosenbergMW, DePinhoRA (2001) Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 28 : 155–159.
67. GossKH, RisingerMA, KordichJJ, SanzMM, StraughenJE, et al. (2002) Enhanced tumor formation in mice heterozygous for Blm mutation. Science 297 : 2051–2053.
68. MannMB, HodgesCA, BarnesE, VogelH, HassoldTJ, et al. (2005) Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome. Hum Mol Genet 14 : 813–825.
69. DuursmaAM, KeddeM, SchrierM, le SageC, AgamiR (2008) miR-148 targets human DNMT3b protein coding region. RNA 14 : 872–877.
70. FormanJJ, Legesse-MillerA, CollerHA (2008) A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc Natl Acad Sci U S A 105 : 14879–14884.
71. OromUA, NielsenFC, LundAH (2008) MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell 30 : 460–471.
72. TayY, ZhangJ, ThomsonAM, LimB, RigoutsosI (2008) MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455 : 1124–1128.
73. HafnerM, LandthalerM, BurgerL, KhorshidM, HausserJ, et al. (2010) Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141 : 129–141.
74. RobertsAP, LewisAP, JoplingCL (2011) miR-122 activates hepatitis C virus translation by a specialized mechanism requiring particular RNA components. Nucleic Acids Res 39 : 7716–29.
75. XueX, FengT, YaoS, WolfKJ, LiuCG, et al. (2011) Microbiota downregulates dendritic cell expression of miR-10a, which targets IL-12/IL-23p40. J Immunol 187 : 5879–5886.
76. ChristoffersenNR, ShalgiR, FrankelLB, LeucciE, LeesM, et al. (2010) p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ 17 : 236–245.
77. SmythGK, MichaudJ, ScottHS (2005) Use of within-array replicate spots for assessing differential expression in microarray experiments. Bioinformatics 21 : 2067–2075.
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