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Germline Genetic Variants Disturbing the /LIN28 Double-Negative Feedback Loop Alter Breast Cancer Susceptibility


Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7–induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0×10−5. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk.


Vyšlo v časopise: Germline Genetic Variants Disturbing the /LIN28 Double-Negative Feedback Loop Alter Breast Cancer Susceptibility. PLoS Genet 7(9): e32767. doi:10.1371/journal.pgen.1002259
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002259

Souhrn

Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7–induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0×10−5. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk.


Zdroje

1. BartelDP 2004 MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 116 281 297

2. Esquela-KerscherASlackFJ 2006 Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6 259 269

3. BussingISlackFJGrosshansH 2008 let-7 microRNAs in development, stem cells and cancer. Trends Mol Med 14 400 409

4. JohnsonSMGrosshansHShingaraJByromMJarvisR 2005 RAS is regulated by the let-7 MicroRNA family. Cell 120 635 647

5. SampsonVBRongNHHanJYangQYArisV 2007 MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res 67 9762 9770

6. LeeYSDuttaA 2007 The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Gene Dev 21 1025 1030

7. YuFYaoHZhuPCZhangXQPanQH 2007 Iet-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131 1109 1123

8. ViswanathanSRDaleyGQ 2010 Lin28: A MicroRNA Regulator with a Macro Role. Cell 140 445 449

9. YuJYVodyanikMASmuga-OttoKAntosiewicz-BourgetJFraneJL 2007 Induced pluripotent stem cell lines derived from human somatic cells. Science 318 1917 1920

10. ViswanathanSRPowersJTEinhornWHoshidaYNgTL 2009 Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 41 843 848

11. RybakAFuchsHSmirnovaLBrandtCPohlEE 2008 A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nat Cell Biol 10 987 993

12. YangXJLinXJZhongXMKaurSLiN 2010 Double-Negative Feedback Loop between Reprogramming Factor LIN28 and microRNA let-7 Regulates Aldehyde Dehydrogenase 1-Positive Cancer Stem Cells. Cancer Res 70 9463 9472

13. ViswanathanSRDaleyGQGregoryRI 2008 Selective blockade of MicroRNA processing by Lin28. Science 320 97 100

14. HaganJPPiskounovaEGregoryRI 2009 Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat Struct Mol Biol 16 1021 1025

15. HeoIJooCChoJHaMHanJJ 2008 Lin28 Mediates the Terminal Uridylation of let-7 Precursor MicroRNA. Mol Cell 32 276 284

16. NewmanMAThomsonJMHammondSM 2008 Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 14 1539 1549

17. Dangi-GarimellaSYunJEvesEMNewmanMErkelandSJ 2009 Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J 28 347 358

18. IliopoulosDHirschHAStruhlK 2009 An Epigenetic Switch Involving NF-kappa B, Lin28, Let-7 MicroRNA, and IL6 Links Inflammation to Cell Transformation. Cell 139 693 706

19. ChinLJRatnerELengSGZhaiRHNallurS 2008 A SNP in a let-7 microRNA Complementary Site in the KRAS 3′ Untranslated Region Increases Non-Small Cell Lung Cancer Risk. Cancer Res 68 8535 8540

20. SaetromPBiesingerJLiSMSmithDThomasLF 2009 A Risk Variant in an miR-125b Binding Site in BMPR1B Is Associated with Breast Cancer Pathogenesis. Cancer Res 69 7459 7465

21. LiangDMeyerLChangDWLinJPuX 2010 Genetic Variants in MicroRNA Biosynthesis Pathways and Binding Sites Modify Ovarian Cancer Risk, Survival, and Treatment Response. Cancer Res 70 9765 9776

22. NicolosoMSSunHSpizzoRKimHWickramasingheP 2010 Single-Nucleotide Polymorphisms Inside MicroRNA Target Sites Influence Tumor Susceptibility. Cancer Res 70 2789 2798

23. WalshTKingMC 2007 Ten genes for inherited breast cancer. Cancer Cell 11 103 105

24. KerteszMIovinoNUnnerstallUGaulUSegalE 2007 The role of site accessibility in microRNA target recognition. Nat Genet 39 1278 1284

25. YuKDDiGHYuanWTFanLWuJ 2009 Functional polymorphisms, altered gene expression and genetic association link NRH∶quinone oxidoreductase 2 to breast cancer with wild-type p53. Hum Mol Genet 18 2502 2517

26. ZhaoYCDengCSWangJRXiaoJGatalicaZ 2011 Let-7 family miRNAs regulate estrogen receptor alpha signaling in estrogen receptor positive breast cancer. Breast Cancer Res Treat 127 69 80

27. StrattonMRRahmanN 2008 The emerging landscape of breast cancer susceptibility. Nat Genet 40 17 22

28. GibbsRABelmontJWHardenbolPWillisTDYuFL 2003 The International HapMap Project. Nature 426 789 796

29. YuKDDiGHFanLWuJHuZ 2009 A functional polymorphism in the promoter region of GSTM1 implies a complex role for GSTM1 in breast cancer. FASEB J 23 2274 2287

30. SaundersMALiangHLiWH 2007 Human polymorphism at microRNAs and microRNA target sites. P Natl Acad Sci USA 104 3300 3305

31. MishraPJBertinoJR 2009 MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics 10 399 416

32. XieXHLuJKulbokasEJGolubTRMoothaV 2005 Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434 338 345

33. MorroghMOlveraNBogomolniyFBorgenPIKingTA 2007 Tissue preparation for laser capture microdissection and RNA extraction from fresh frozen breast tissue. Biotechniques 43 41 48

34. CareyLAPerouCMLivasyCADresslerLGCowanD 2006 Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295 2492 2502

35. YinWJLuJSDiGHLinYPZhouLH 2009 Clinicopathological features of the triple-negative tumors in Chinese breast cancer patients. Breast Cancer Res Treat 115 325 333

36. ZhuTEmeraldBSZhangXLeeKOGluckmanPD 2005 Oncogenic transformation of human mammary epithelial cells by autocrine human growth hormone. Cancer Res 65 317 324

37. BarrettJCFryBMallerJDalyMJ 2005 Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 263 265

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