miR-100 Induces Epithelial-Mesenchymal Transition but Suppresses Tumorigenesis, Migration and Invasion

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Whether epithelial-mesenchymal transition (EMT) is always linked to increased tumorigenicity is controversial. Through microRNA (miRNA) expression profiling of mammary epithelial cells overexpressing Twist, Snail or ZEB1, we identified miR-100 as a novel EMT inducer. Surprisingly, miR-100 inhibits the tumorigenicity, motility and invasiveness of mammary tumor cells, and is commonly downregulated in human breast cancer due to hypermethylation of its host gene MIR100HG. The EMT-inducing and tumor-suppressing effects of miR-100 are mediated by distinct targets. While miR-100 downregulates E-cadherin by targeting SMARCA5, a regulator of CDH1 promoter methylation, this miRNA suppresses tumorigenesis, cell movement and invasion in vitro and in vivo through direct targeting of HOXA1, a gene that is both oncogenic and pro-invasive, leading to repression of multiple HOXA1 downstream targets involved in oncogenesis and invasiveness. These findings provide a proof-of-principle that EMT and tumorigenicity are not always associated and that certain EMT inducers can inhibit tumorigenesis, migration and invasion.

Vyšlo v časopise: miR-100 Induces Epithelial-Mesenchymal Transition but Suppresses Tumorigenesis, Migration and Invasion. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004177
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004177

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Zdroje

1. ThieryJP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.

2. YangJ, WeinbergRA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14: 818–829.

3. ScheelC, OnderT, KarnoubA, WeinbergRA (2007) Adaptation versus selection: the origins of metastatic behavior. Cancer Res 67: 11476–11479 discussion 11479–11480.

4. GregoryPA, BertAG, PatersonEL, BarrySC, TsykinA, et al. (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10: 593–601.

5. ParkSM, GaurAB, LengyelE, PeterME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22: 894–907.

6. ShimonoY, ZabalaM, ChoRW, LoboN, DalerbaP, et al. (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138: 592–603.

7. WellnerU, SchubertJ, BurkUC, SchmalhoferO, ZhuF, et al. (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11: 1487–1495.

8. ZhangJ, MaL (2012) MicroRNA control of epithelial-mesenchymal transition and metastasis. Cancer Metastasis Rev 31: 653–662.

9. MaL, YoungJ, PrabhalaH, PanE, MestdaghP, et al. (2010) miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12: 247–256.

10. BrabletzT (2012) To differentiate or not–routes towards metastasis. Nat Rev Cancer 12: 425–436.

11. TsaiJH, DonaherJL, MurphyDA, ChauS, YangJ (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22: 725–736.

12. OcanaOH, CorcolesR, FabraA, Moreno-BuenoG, AcloqueH, et al. (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22: 709–724.

13. ManiSA, GuoW, LiaoMJ, EatonEN, AyyananA, et al. (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133: 704–715.

14. MorelAP, LievreM, ThomasC, HinkalG, AnsieauS, et al. (2008) Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 3: e2888.

15. Celia-TerrassaT, Meca-CortesO, MateoF, de PazAM, RubioN, et al. (2012) Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J Clin Invest 122: 1849–1868.

16. ElenbaasB, SpirioL, KoernerF, FlemingMD, ZimonjicDB, et al. (2001) Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev 15: 50–65.

17. Comprehensive molecular portraits of human breast tumours. Nature 490: 61–70.

18. SunD, LeeYS, MalhotraA, KimHK, MatecicM, et al. (2011) miR-99 family of MicroRNAs suppresses the expression of prostate-specific antigen and prostate cancer cell proliferation. Cancer Res 71: 1313–1324.

19. ZengY, QuX, LiH, HuangS, WangS, et al. (2012) MicroRNA-100 regulates osteogenic differentiation of human adipose-derived mesenchymal stem cells by targeting BMPR2. FEBS Lett 586: 2375–2381.

20. ZhangX, ZhuT, ChenY, MertaniHC, LeeKO, et al. (2003) Human growth hormone-regulated HOXA1 is a human mammary epithelial oncogene. J Biol Chem 278: 7580–7590.

21. ChariotA, CastronovoV (1996) Detection of HOXA1 expression in human breast cancer. Biochem Biophys Res Commun 222: 292–297.

22. GeimanTM, SankpalUT, RobertsonAK, ZhaoY, RobertsonKD (2004) DNMT3B interacts with hSNF2H chromatin remodeling enzyme, HDACs 1 and 2, and components of the histone methylation system. Biochem Biophys Res Commun 318: 544–555.

23. ScottKL, NogueiraC, HeffernanTP, van DoornR, DhakalS, et al. (2011) Proinvasion metastasis drivers in early-stage melanoma are oncogenes. Cancer Cell 20: 92–103.

24. ChisakaO, MusciTS, CapecchiMR (1992) Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature 355: 516–520.

25. LufkinT, DierichA, LeMeurM, MarkM, ChambonP (1991) Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell 66: 1105–1119.

26. MakkiN, CapecchiMR (2011) Identification of novel Hoxa1 downstream targets regulating hindbrain, neural crest and inner ear development. Dev Biol 357: 295–304.

27. GherardiE, BirchmeierW, BirchmeierC, Vande WoudeG (2012) Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12: 89–103.

28. KalderonD (2000) Transducing the hedgehog signal. Cell 103: 371–374.

29. BermanDM, KarhadkarSS, HallahanAR, PritchardJI, EberhartCG, et al. (2002) Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297: 1559–1561.

30. EsselensC, MalapeiraJ, ColomeN, CasalC, Rodriguez-ManzanequeJC, et al. (2010) The cleavage of semaphorin 3C induced by ADAMTS1 promotes cell migration. J Biol Chem 285: 2463–2473.

31. HermanJG, MeadowsGG (2007) Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells. Int J Oncol 30: 1231–1238.

32. SicinskiP, DonaherJL, ParkerSB, LiT, FazeliA, et al. (1995) Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82: 621–630.

33. WangTC, CardiffRD, ZukerbergL, LeesE, ArnoldA, et al. (1994) Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369: 669–671.

34. GrahamTR, YacoubR, Taliaferro-SmithL, OsunkoyaAO, Odero-MarahVA, et al. (2010) Reciprocal regulation of ZEB1 and AR in triple negative breast cancer cells. Breast Cancer Res Treat 123: 139–147.

35. KarihtalaP, AuvinenP, KauppilaS, HaapasaariKM, Jukkola-VuorinenA, et al. (2013) Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotype. Breast Cancer Res Treat 138: 81–90.

36. MaL, Teruya-FeldsteinJ, WeinbergRA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449: 682–688.

37. NilssonJA, ClevelandJL (2003) Myc pathways provoking cell suicide and cancer. Oncogene 22: 9007–9021.

38. GinestierC, HurMH, Charafe-JauffretE, MonvilleF, DutcherJ, et al. (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1: 555–567.

39. DontuG, AbdallahWM, FoleyJM, JacksonKW, ClarkeMF, et al. (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17: 1253–1270.

40. GebeshuberCA, MartinezJ (2013) miR-100 suppresses IGF2 and inhibits breast tumorigenesis by interfering with proliferation and survival signaling. Oncogene 32: 3306–3310.

41. SongSJ, PolisenoL, SongMS, AlaU, WebsterK, et al. (2013) MicroRNA-Antagonism Regulates Breast Cancer Stemness and Metastasis via TET-Family-Dependent Chromatin Remodeling. Cell 154: 311–324.

42. StewartSA, DykxhoornDM, PalliserD, MizunoH, YuEY, et al. (2003) Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 9: 493–501.

43. LewisBP, BurgeCB, BartelDP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.

44. RehmsmeierM, SteffenP, HochsmannM, GiegerichR (2004) Fast and effective prediction of microRNA/target duplexes. RNA 10: 1507–1517.