Skip to main content

Advertisement

SpringerLink
Log in

Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5

  • Original Articles
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

A number of microRNAs (miRNAs), including miR-200 family, are aberrantly expressed in endometriosis and endometrial cancer. Here we assessed the expression and functional aspects of miR-200c in endometrial tissues (N = 52) from normal endometrial biopsies (N = 15), endometrial tissues including those exposed to hormonal therapies (N = 20), and grade I-III endometrial cancer (N = 17). miR-200c expression was elevated in normal endometrial biopsies from mid- and late-luteal phase, and in endometrial tumors as compared to endometrial tissues from peri- and postmenopausal period (P < .05) and its pattern of temporal expression displayed an inverse relationship with the expression of ZEBs. The expression of E-cadherin (CDH1) varied, but expressed at low levels, specifically in endometrial tissues and endometrial tumors. The endometrial expression of ZEBs and CDH1 in patients who were exposed to Depo-Provera and gonadotropin-releasing hormone agonist GnRHa displayed a trend toward lower expression as compared to proliferative phase; however, treatment of Ishikawa cells with 17β-estradiol, progesterone, and medroxy progesterone acetate had modest effects on the expression of miR-200c and ZEBs without affecting CDH1 expression. Gain of function of miR-200c in Ishikawa cells repressed ZEBs, as well as VEGFA, FLT1, IKKβ, and KLF9 expression at transcriptional and translational levels through direct interaction with their respective 3′untranslated regions and increased the rate of their proliferation. These results indicated that endometrial miR-200c expression undergoes dynamic changes during transition from normal into cancerous states; possibly influenced by hormonal milieu and by targeting the expression of specific genes with key regulatory functions in cellular transformation, inflammation, and angiogenesis may influence these events during normal and disease progression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Djuranovic S, Nahvi A, Green R. A parsimonious model for gene regulation by miRNAs. Science. 2011;331(6017):550–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dykxhoorn DM. MicroRNAs and metastasis: little RNAs go a long way. Cancer Res. 2010;70(16):6401–6406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010;79:351–379.

    Article  CAS  PubMed  Google Scholar 

  4. Schickel R, Boyerinas B, Park SM, Peter ME. MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene. 2008;27(45):5959–5974.

    Article  CAS  PubMed  Google Scholar 

  5. Brabletz S, Brabletz T. The ZEB/miR-200 feedback loop—a motor of cellular plasticity in development and cancer? EMBO Rep. 2010;ll(9):670–677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011;469(7330):336–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gonzalez G, Behringer RR. Dicer is required for female reproductive tract development and fertility in the mouse. Mol Reprod Dev. 2009;76(7):678–688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hong X, Luense LJ, McGinnis LK, Nothnick WB, Christenson LK. Dicerl is essential for female fertility and normal development of the female reproductive system. Endocrinology. 2008; 149(12):6207–6212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nagaraja AK, Andreu-Vieyra C, Franco HL, et al. Deletion of Dicer in somatic cells of the female reproductive tract causes sterility. Mol Endocrinol. 2008;22(10):2336–2352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Boren T, Xiong Y, Hakam A, et al. MicroRNAs and their target messenger RNAs associated with endometrial carcinogenesis. Gynecol Oncol. 2008;110(2):206–215.

    Article  CAS  PubMed  Google Scholar 

  11. Cohn DE, Fabbri M, Valeri N, et al. Comprehensive miRNA profiling of surgically staged endometrial cancer. Am J Obstet Gynecol. 2010;202(6):656–658.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Hawkins SM, Buchold GM, Matzuk MM. Minireview: the roles of small RNA pathways in reproductive medicine. Mol Endocrinol. 2011;25(8): 1257–1279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hawkins SM, Creighton CJ, Han DY, et al. Functional Micro-RNA Involved in Endometriosis. Mol Endocrinol. 2011;25(5): 821–832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Myatt SS, Wang J, Monteiro LJ, et al. Definition of microRNAs that repress expression of the tumor suppressor gene FOXOl in endometrial cancer. Cancer Res. 2010;70(l):367–377.

    Article  CAS  PubMed  Google Scholar 

  15. Ohlsson Teague EM, Van der Hoek KH, Van der Hoek MB, et al. MicroRNA-regulated pathways associated with endometriosis. Mol Endocrinol. 2009;23(2):265–275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Pan Q, Luo X, Toloubeydokhti T, Chegini N. The expression profile of micro-RNA in endometrium and endometriosis and the influence of ovarian steroids on their expression. Mol Hum Reprod. 2007;13(ll):797–806.

    Article  CAS  PubMed  Google Scholar 

  17. Ramon LA, Braza-Boils A, Gilabert-Estelles J, et al. MicroRNAs expression in endometriosis and their relation to angiogenic factors. Hum Reprod. 2011;26(5):1082–1090.

    Article  CAS  PubMed  Google Scholar 

  18. Castilla MA, Moreno-Bueno G, Romero-Perez L, et al. Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma. J Pathol. 2011;223(l):72–80.

    Article  CAS  PubMed  Google Scholar 

  19. Cochrane DR, Howe EN, Spoelstra NS, Richer JK. Loss of miR-200c: a marker of aggressiveness and chemoresistance in female reproductive cancers. J Oncol. 2010;2010:821717.

    Article  PubMed  CAS  Google Scholar 

  20. Filigheddu N, Gregnanin I, Porporato PE, et al. Differential expression of microRNAs between eutopic and ectopic endometrium in ovarian endometriosis. J Biomed Biotechnol. 2010; 2010:369549.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Kuokkanen S, Chen B, Ojalvo L, Benard L, Santoro N, Pollard JW. Genomic profiling of microRNAs and messenger RNAs reveals hormonal regulation in microRNA expression in human endometrium. Biol Reprod. 2010;82(4):791–801.

    Article  CAS  PubMed  Google Scholar 

  22. Lee JW, Park YA, Choi JJ, et al. The expression of the miRNA-200 family in endometrial endometrioid carcinoma. Gynecol Oncol. 201 l;120(l):56–62.

    Article  CAS  PubMed  Google Scholar 

  23. Davalos V, Esteller M. Opening the treasure chest of miR-200 s family members. Cell Cycle. 2009;8(14):2141–2142.

    Article  CAS  PubMed  Google Scholar 

  24. Chan YC, Khanna S, Roy S, Sen CK. miR-200b targets Ets-1 and is down-regulated by hypoxia to induce angiogenic response of endothelial cells. J Biol Chem. 2011;286(3):2047–2056.

    Article  CAS  PubMed  Google Scholar 

  25. Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K. Loss of miR-200 inhibition of Suzl2 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell. 2010;39(5): 761–772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kong D, Li Y, Wang Z, et al. miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells. 2009;27(8): 1712–1721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Korpal M, Ell BJ, Buffa FM, et al. Direct targeting of Sec23a by miR-200 s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 2011;17(9):1101–1108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Roybal JD, Zang Y, Ahn YH, et al. miR-200 Inhibits lung adenocarcinoma cell invasion and metastasis by targeting Fltl/ VEGFR1. Mol Cancer Res. 2011;9(l):25–35.

    Article  CAS  PubMed  Google Scholar 

  29. Uhlmann S, Zhang JD, Schwager A, et al. miR-200bc/429 cluster targets PLCgammal and differentially regulates proliferation and EGF-driven invasion than miR-200a/141 in breast cancer. Oncogene. 2010;29(30):4297–4306.

    Article  CAS  PubMed  Google Scholar 

  30. Wang B, Koh P, Winbanks C, et al. miR-200a prevents renal fibrogenesis through repression of TGF-beta2 expression. Diabetes. 201;60(1):280–287.

    Article  CAS  PubMed  Google Scholar 

  31. Renthal NE, Chen CC, Williams KC, Gerard RD, Prange-Kiel J, Mendelson CR. miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. Proc Natl Acad Sci USA. 2010;107(48):20828–20833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dahiya N, Sherman-Baust CA, Wang TL, et al. MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PLoS One. 2008;3(6):e2436.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Inomata M, Tagawa H, Guo YM, Kameoka Y, Takahashi N, Sawada K. MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes. Blood. 2009;113(2):396–402.

    Article  CAS  PubMed  Google Scholar 

  34. Chen R, Alvero AB, Silasi DA, et al. Regulation of IKK[beta] by miR-199a affects NF-[kappa]B activity in ovarian cancer cells. Oncogene. 2008;27(34):4712–4723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Spoelstra NS, Manning NG, Higashi Y, et al. The transcription factor ZEB1 is aberrantly expressed in aggressive uterine cancers. Cancer Res. 2006;66(7):3893–3902.

    Article  CAS  PubMed  Google Scholar 

  36. Singh M, Spoelstra NS, Jean A, et al. ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol. 2008;21(7):912–923.

    Article  CAS  PubMed  Google Scholar 

  37. Snowdon J, Zhang X, Childs T, Tron VA, Feilotter H. The microRNA-200 family is upregulated in endometrial carcinoma. PLoS One. 2011;6(8):e22828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Spoelstra NS, Manning NG, Higashi Y. The transcription factor ZEB1 is aberrantly expressed in aggressive uterine cancers. Cancer Res. 2006;66(7):3893–3902.

    Article  CAS  PubMed  Google Scholar 

  39. Yoshimoto N, Toyama T, Takahashi S, et al. Distinct expressions of microRNAs that directly target estrogen receptor alpha in human breast cancer. Breast Cancer Res Treat. 2011;130(1): 331–339.

    Article  CAS  PubMed  Google Scholar 

  40. Bendoraite A, Knouf EC, Garg KS, et al. Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition. Gynecol Oncol. 2010;116(1): 117–125.

    Article  CAS  PubMed  Google Scholar 

  41. Brabletz S, Bajdak K, Meidhof S, et al. The ZEBl/miR-200 feedback loop controls Notch signalling in cancer cells. EMBO J. 2011;30(4):770–782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dykxhoorn DM, Wu Y, Xie H, et al. miR-200 enhances mouse breast cancer cell colonization to form distant metastases. PLoS One. 2009;4(9):e7181.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593-601.

    Article  CAS  PubMed  Google Scholar 

  44. Xia H, Ng SS, Jiang S, et al. miR-200a-mediated downregulation of ZEB2 and CTNNB1 differentially inhibits nasopharyngeal carcinoma cell growth, migration and invasion. Biochem Biophys Res Commun. 2010;391(1):535–541.

    Article  CAS  PubMed  Google Scholar 

  45. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119(6): 1420–1428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139(5):871–890.

    Article  CAS  PubMed  Google Scholar 

  47. Vandewalle C, Comijn J, De CB, et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res. 2005;33(20):6566–6578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen SU, Lee H, Chang DY, et al. Lysophosphatidic acid mediates interleukin-8 expression in human endometrial stromal cells through its receptor and nuclear factor-kappaB-dependent pathway: a possible role in angiogenesis of endometrium and placenta. Endocrinology. 2008; 149(11): 5888–5896.

    Article  CAS  PubMed  Google Scholar 

  49. Graesslin O, Cortez A, Fauvet R, Lorenzato M, Birembaut P, Darai E. Metalloproteinase-2, -7 and -9 and tissue inhibitor of metalloproteinase-1 and -2 expression in normal, hyperplastic and neoplastic endometrium: a clinical-pathological correlation study. Ann Oncol. 2006;17(4):637–645.

    Article  CAS  PubMed  Google Scholar 

  50. Hannan NJ, Paiva P, Meehan KL, Rombauts LJ, Gardner DK, Salamonsen LA. Analysis of fertility-related soluble mediators in human uterine fluid identifies VEGF as a key regulator of embryo implantation. Endocrinology. 2011;152(12):4948–4956.

    Article  CAS  PubMed  Google Scholar 

  51. Huang F, Liu Q, Wang H, Zou Y. Effect of GnRH II and GnRH I on secretion of VEGF by eutopic and ectopic endometrial stromal cells of endometriosis patients. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010;35(5):409–418.

    CAS  PubMed  Google Scholar 

  52. King AE, Critchley HO, Kelly RW. The NF-kappaB pathway in human endometrium and first trimester decidua. Mol Hum Reprod. 2001;7(2):175–183.

    Article  CAS  PubMed  Google Scholar 

  53. Maybin JA, Hirani N, Jabbour HN, Critchley HO. Novel roles for hypoxia and prostaglandin E2 in the regulation of IL-8 during endometrial repair. Am J Pathol. 2011;178(3): 1245–1256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Maybin JA, Hirani N, Brown P, Jabbour HN, Critchley HO. The regulation of vascular endothelial growth factor by hypoxia and prostaglandin Falpha during human endometrial repair. J Clin Endocrinol Metab. 2011;96(8):2475–2483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Okada H, Okamoto R, Tsuzuki T, Tsuji S, Yasuda K, Kanzaki H. Progestins inhibit estradiol-induced vascular endothelial growth factor and stromal cell-derived factor 1 in human endometrial stromal cells. Fertil Steril. 2011;96(3):786–791.

    Article  CAS  PubMed  Google Scholar 

  56. Simmen RC, Pabona JM, Velarde MC, Simmons C, Rahal O, Simmen FA. The emerging role of Kruppel-like factors in endocrine-responsive cancers of female reproductive tissues. J Endocrinol. 2010;204(3):223–231.

    Article  CAS  PubMed  Google Scholar 

  57. Taylor RN, Yu J, Torres PB, et al. Mechanistic and therapeutic implications of angiogenesis in endometriosis. Reprod Sci. 2009;16(2):140–146.

    Article  CAS  PubMed  Google Scholar 

  58. Ulukus M, Ulukus EC, Tavmergen Goker EN, Tavmergen E, Zheng W, Arici A. Expression of interleukin-8 and monocyte che-motactic protein 1 in women with endometriosis. Fertil Steril. 2009;91(3):687–693.

    Article  CAS  PubMed  Google Scholar 

  59. Dai L, Gu L, Di W. MiR-199a attenuates endometrial stromal cell invasiveness through suppression of the IKK{beta}/NF-kB pathway and reduced interleukin-8 expression. Mol Hum Reprod. 2011;18(3):136–145.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Julien S, Puig I, Caretti E, et al. Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene. 2007;26(53):7445–7456.

    Article  CAS  PubMed  Google Scholar 

  61. Du H, Sarno J, Taylor HS. HOXA10 inhibits Kruppel-like factor 9 expression in the human endometrial epithelium. Biol Reprod. 2010;83(2):205–211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Simmons CD, Pabona JM, Heard ME, et al. Kruppel-like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen. Biol Reprod. 2011;85(2): 378–385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Orhan Bukulmez MD

    Present address: Present address; Department of OB/GYN, University of Texas Southwestern Medical Center, Dallas, TX, USA

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Florida, PO Box 100294, Gainesville, FL, 32610, USA

    Harekrushna Panda PhD, Leslie Pelakh BS, Tsai-Der Chuang PhD, Xiaoping Luo MD, Orhan Bukulmez MD & Nasser Chegini PhD

Authors
  1. Harekrushna Panda PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leslie Pelakh BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tsai-Der Chuang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoping Luo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Orhan Bukulmez MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nasser Chegini PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nasser Chegini PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Panda, H., Pelakh, L., Chuang, TD. et al. Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5. Reprod. Sci. 19, 786–796 (2012). https://doi.org/10.1177/1933719112438448

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719112438448

Keywords

Search

Navigation