Tumor Biology

, Volume 37, Issue 7, pp 9157–9167 | Cite as

MiR-381 inhibits epithelial ovarian cancer malignancy via YY1 suppression

  • Bairong Xia
  • Huiyan Li
  • Shanshan Yang
  • Tianbo Liu
  • Ge Lou
Original Article


Epithelial ovarian cancer (EOC) is a common type of gynecologic cancer, which accounts for the majority of deaths among all gynecologic malignant tumors in developed countries. A series of recent studies suggested that miR-381 might play important roles in the development of various cancer types. However, the biological function of miR-381 in EOC remains to be investigated. We examined the levels of miR-381 expression in EOC tissues and cell lines. We identified miR-381 target genes by bioinformatic prediction. We also characterized the phenotype regarding cell proliferation, cell migration, and cell invasion in EOC cells lines with altered expression levels of both miR-381 and its target gene, YY1. The expression levels of miR-381 were downregulated in EOC tissues and cell lines. Overexpression of miR-381 significantly inhibited EOC cell proliferation, migration, and invasion. Restoration of YY1 expression partially reversed the phenotype induced by miR-381 overexpression. Knockdown of miR-381 target gene, YY1, mimicked the phenotype induced by miR-381 overexpression. MiR-381 regulated EOC cell through miR-381/YY1/p53 and miR-381/YY1/Wnt signaling axis. We concluded that miR-381 inhibited EOC cell proliferation, migration, and invasion, at least in part, via suppressing YY1 expression.


miR-381 YY1 Epithelial ovarian cancer Cell proliferation Cell migration Cell invasion 



This study was supported by grants from National Natural Science Foundation of China (no. 81472028).

Compliance with ethical standards

This study was approved by the Medical Ethics Committee of the Affiliated Tumor Hospital of Harbin Medical University and all patients were provided informed consent.

Conflicts of interest


Supplementary material

13277_2016_4805_Fig8_ESM.gif (18 kb)
Supplemental figure 1

miR-381 decreases downstream genes of Wnt signaling pathway in both SKOV3 and COV644 cells. *p < 0.05 compared to miR-Ctrl transfected cells (GIF 17 kb)

13277_2016_4805_MOESM1_ESM.tif (745 kb)
High resolution (TIF 744 kb)


  1. 1.
    Granato T, Midulla C, Longo F, Colaprisca B, Frati L, Anastasi E. Role of he4, ca72.4, and ca125 in monitoring ovarian cancer. Tumour Biol J Int Soc Oncodevelopmental Biol Med. 2012;33:1335–9.CrossRefGoogle Scholar
  2. 2.
    Bristow RE. Surgical standards in the management of ovarian cancer. Curr Opin Oncol. 2000;12:474–80.CrossRefPubMedGoogle Scholar
  3. 3.
    Chang SJ, Bristow RE. Evolution of surgical treatment paradigms for advanced-stage ovarian cancer: redefining 'optimal' residual disease. Gynecol Oncol. 2012;125:483–92.CrossRefPubMedGoogle Scholar
  4. 4.
    Harter P, Muallem ZM, Buhrmann C, Lorenz D, Kaub C, Hils R, et al. Impact of a structured quality management program on surgical outcome in primary advanced ovarian cancer. Gynecol Oncol. 2011;121:615–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Harries M, Gore M. Part i: chemotherapy for epithelial ovarian cancer-treatment at first diagnosis. Lancet Oncol. 2002;3:529–36.CrossRefPubMedGoogle Scholar
  6. 6.
    Matei DE, Nephew KP. Epigenetic therapies for chemoresensitization of epithelial ovarian cancer. Gynecol Oncol. 2010;116:195–201.CrossRefPubMedGoogle Scholar
  7. 7.
    Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microrna biogenesis pathways and their regulation. Nat Cell Biol. 2009;11:228–34.CrossRefPubMedGoogle Scholar
  8. 8.
    Osada H, Takahashi T. Micrornas in biological processes and carcinogenesis. Carcinogenesis. 2007;28:2–12.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhang Q, Tang Q, Qin D, Yu L, Huang R, Lv G, et al. Role of microrna 30a targeting insulin receptor substrate 2 in colorectal tumorigenesis. Mol Cell Biol. 2015;35:988–1000.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sui X, Wang X, Han W, Li D, Xu Y, Lou F, et al. Micrornas-mediated cell fate in triple negative breast cancers. Cancer Lett. 2015;361:8–12.CrossRefPubMedGoogle Scholar
  11. 11.
    Iorio MV, Croce CM. Microrna involvement in human cancer. Carcinogenesis. 2012;33:1126–33.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lee SH, Jung YD, Choi YS, Lee YM. Targeting of runx3 by mir-130a and mir-495 cooperatively increases cell proliferation and tumor angiogenesis in gastric cancer cells. Oncotarget. 2015.Google Scholar
  13. 13.
    Guo M, Zhang X, Wang G, Sun J, Jiang Z, Khadarian K, et al. Mir-603 promotes glioma cell growth via wnt/beta-catenin pathway by inhibiting wif1 and ctnnbip1. Cancer Lett. 2015;360:76–86.CrossRefPubMedGoogle Scholar
  14. 14.
    Liu YN, Yin J, Barrett B, Sheppard-Tillman H, Li D, Casey OM, et al. Loss of androgen-regulated microrna 1 activates src and promotes prostate cancer bone metastasis. Mol Cell Biol. 2015;35:1940–51.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Li X, Li H, Zhang R, Liu J. Microrna-449a inhibits proliferation and induces apoptosis by directly repressing e2f3 in gastric cancer. Cell Physiol Biochem Int J Exp Cell Physiol, Biochem Pharmacol. 2015;35:2033–42.CrossRefGoogle Scholar
  16. 16.
    Tang H, Liu X, Wang Z, She X, Zeng X, Deng M, et al. Interaction of hsa-mir-381 and glioma suppressor lrrc4 is involved in glioma growth. Brain Res. 2011;1390:21–32.CrossRefPubMedGoogle Scholar
  17. 17.
    Liang Y, Zhao Q, Fan L, Zhang Z, Tan B, Liu Y, et al. Down-regulation of microrna-381 promotes cell proliferation and invasion in colon cancer through up-regulation of lrh-1. Biomed Pharmacother Biomed Pharmacotherapie. 2015;75:137–41.CrossRefGoogle Scholar
  18. 18.
    Rothschild SI, Tschan MP, Jaggi R, Fey MF, Gugger M, Gautschi O. Microrna-381 represses id1 and is deregulated in lung adenocarcinoma. J Thorac Oncol : Off Publ Int Assoc Study Lung Cancer. 2012;7:1069–77.CrossRefGoogle Scholar
  19. 19.
    Chen B, Liu B. [mirna-381 inhibits the invasion of renal carcinoma and the underlying mechanisms]. Zhong nan da xue xue bao Yi xue ban J Cent South Univ Med Sci. 2015;40:1053–9.Google Scholar
  20. 20.
    Chen B, Duan L, Yin G, Tan J, Jiang X. Simultaneously expressed mir-424 and mir-381 synergistically suppress the proliferation and survival of renal cancer cells—cdc2 activity is up-regulated by targeting wee1. Clinics. 2013;68:825–33.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Donohoe ME, Zhang X, McGinnis L, Biggers J, Li E, Shi Y. Targeted disruption of mouse yin yang 1 transcription factor results in peri-implantation lethality. Mol Cell Biol. 1999;19:7237–44.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Shi Y, Seto E, Chang LS, Shenk T. Transcriptional repression by yy1, a human gli-kruppel-related protein, and relief of repression by adenovirus e1a protein. Cell. 1991;67:377–88.CrossRefPubMedGoogle Scholar
  23. 23.
    Gordon S, Akopyan G, Garban H, Bonavida B. Transcription factor yy1: structure, function, and therapeutic implications in cancer biology. Oncogene. 2006;25:1125–42.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang Q, Stovall DB, Inoue K, Sui G. The oncogenic role of yin yang 1. Crit Rev Oncog. 2011;16:163–97.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sui G, el Affar B, Shi Y, Brignone C, Wall NR, Yin P, et al. Yin yang 1 is a negative regulator of p53. Cell. 2004;117:859–72.CrossRefPubMedGoogle Scholar
  26. 26.
    Yakovleva T, Kolesnikova L, Vukojevic V, Gileva I, Tan-No K, Austen M, et al. Yy1 binding to a subset of p53 DNA-target sites regulates p53-dependent transcription. Biochem Biophys Res Commun. 2004;318:615–24.CrossRefPubMedGoogle Scholar
  27. 27.
    Yokoyama NN, Pate KT, Sprowl S, Waterman ML. A role for yy1 in repression of dominant negative lef-1 expression in colon cancer. Nucleic Acids Res. 2010;38:6375–88.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhang N, Li X, Wu CW, Dong Y, Cai M, Mok MT, et al. Microrna-7 is a novel inhibitor of yy1 contributing to colorectal tumorigenesis. Oncogene. 2013;32:5078–88.CrossRefPubMedGoogle Scholar
  29. 29.
    Kang W, Tong JH, Chan AW, Zhao J, Dong Y, Wang S, et al. Yin yang 1 contributes to gastric carcinogenesis and its nuclear expression correlates with shorter survival in patients with early stage gastric adenocarcinoma. J Transl Med. 2014;12:80.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tang H, Wang Z, Liu Q, Liu X, Wu M, Li G. Disturbing mir-182 and −381 inhibits brd7 transcription and glioma growth by directly targeting lrrc4. PLoS One. 2014;9, e84146.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Liang HQ, Wang RJ, Diao CF, Li JW, Su JL, Zhang S. The pttg1-targeting mirnas mir-329, mir-300, mir-381, and mir-655 inhibit pituitary tumor cell tumorigenesis and are involved in a p53/pttg1 regulation feedback loop. Oncotarget. 2015;6:29413–27.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Vilming Elgaaen B, Olstad OK, Haug KB, Brusletto B, Sandvik L, Staff AC, et al. Global mirna expression analysis of serous and clear cell ovarian carcinomas identifies differentially expressed mirnas including mir-200c-3p as a prognostic marker. BMC Cancer. 2014;14:80.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Xia B, Yang S, Liu T, Lou G. Mir-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting cyclin d1 and cdk6. Mol Cancer. 2015;14:57.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wang CC, Chen JJ, Yang PC. Multifunctional transcription factor yy1: a therapeutic target in human cancer? Expert Opin Ther Targets. 2006;10:253–66.CrossRefPubMedGoogle Scholar
  35. 35.
    Xu Y, Ohms SJ, Li Z, Wang Q, Gong G, Hu Y, et al. Changes in the expression of mir-381 and mir-495 are inversely associated with the expression of the mdr1 gene and development of multi-drug resistance. PLoS One. 2013;8, e82062.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ramos YF, Stad R, Attema J, Peltenburg LT, van der Eb AJ, Jochemsen AG. Aberrant expression of hdmx proteins in tumor cells correlates with wild-type p53. Cancer Res. 2001;61:1839–42.PubMedGoogle Scholar
  37. 37.
    Ryu SY, Kim K, Lee WS, Kwon HC, Lee KH, Kim CM, et al. Synergistic growth inhibition by combination of adenovirus mediated p53 transfer and cisplatin in ovarian cancer cell lines. J Gynecol Oncol. 2009;20:48–54.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Liu Z, Gersbach E, Zhang X, Xu X, Dong R, Lee P, et al. Mir-106a represses the rb tumor suppressor p130 to regulate cellular proliferation and differentiation in high-grade serous ovarian carcinoma. Mol Cancer Res : MCR. 2013;11:1314–25.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lee MH, Choi BY, Cho YY, Lee SY, Huang Z, Kundu JK, et al. Tumor suppressor p16(ink4a) inhibits cancer cell growth by downregulating eef1a2 through a direct interaction. J Cell Sci. 2013;126:1744–52.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Huang L, Wang HY, Li JD, Wang JH, Zhou Y, Luo RZ, et al. Kpna2 promotes cell proliferation and tumorigenicity in epithelial ovarian carcinoma through upregulation of c-myc and downregulation of foxo3a. Cell Death Dis. 2013;4, e745.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gan Y, Mo Y, Johnston J, Lu J, Wientjes MG, Au JL. Telomere maintenance in telomerase-positive human ovarian skov-3 cells cannot be retarded by complete inhibition of telomerase. FEBS Lett. 2002;527:10–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Oishi T, Kigawa J, Minagawa Y, Shimada M, Takahashi M, Terakawa N. Alteration of telomerase activity associated with development and extension of epithelial ovarian cancer. Obstet Gynecol. 1998;91:568–71.PubMedGoogle Scholar
  43. 43.
    Gatcliffe TA, Monk BJ, Planutis K, Holcombe RF. Wnt signaling in ovarian tumorigenesis. Int J Gynecol Cancer : Off J Int Gynecol Cancer Soc. 2008;18:954–62.CrossRefGoogle Scholar
  44. 44.
    Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mrnas are conserved targets of micrornas. Genome Res. 2009;19:92–105.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, et al. Combinatorial microrna target predictions. Nat Genet. 2005;37:495–500.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Bairong Xia
    • 1
  • Huiyan Li
    • 2
  • Shanshan Yang
    • 1
  • Tianbo Liu
    • 1
  • Ge Lou
    • 1
  1. 1.Department of Gynecology, the Affiliated Tumor HospitalHarbin Medical UniversityHarbinChina
  2. 2.Department of Nursing, the Affiliated Tumor HospitalHarbin Medical UniversityHarbinChina

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