Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA-101 Inhibits Growth of Epithelial Ovarian Cancer by Relieving Chromatin-Mediated Transcriptional Repression of p21waf1/cip1

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

MicroRNA-101 (miR-101) expression is negatively associated with tumor growth and proliferation in several solid epithelial cancers. Enhancer of zeste homolog 2 (EzH2) appears to be a functional target of miR-101. We explore the role of miR-101 and its interaction with EzH2 in epithelial ovarian carcinoma (EOC).

Methods

In situ hybridization (ISH) for miR-101 was performed on EOC patient tissues and normal controls. EOC cell lines were transfected with miR-101 and subjected to growth analysis and clonogenic assays. Cell motility was assessed by Boyden chamber and wound-healing assays. P21waf1/cip1 and EzH2 interaction was assessed by Chromatin Immunoprecipitation (ChIP) assay in MDAH-2774 cells. SCID mice were assessed for tumor burden after injection with miR-101 or control vector-treated MDAH-2774 cells.

Results

ISH analysis revealed a decrease in miR-101 expression in EOC compared with normal tissue. MiR-101 re-expression in EOC cell lines resulted in increased apoptosis, decreased cellular proliferation, invasiveness, and reduced growth of tumor xenografts. CHIP assays revealed that re-expression of miR-101 inhibited the interaction of EzH2 with p21waf1/cip1 promoter.

Conclusions

MiR-101 re-expression appears to have antitumor effects, providing a better understanding of the role of miR-101 in EOC.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

REFERENCES

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun M. Cancer statistics, 2009. CA: A Cancer J Clinicians. 2009;59:225.

    Article  Google Scholar 

  2. McGuire W, Hoskins W, Brady M, Kucera P, Partridge E, Look K, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. New Engl J Med. 1996;334:1.

    Article  PubMed  CAS  Google Scholar 

  3. Aghajanian C. Clinical update: novel targets in gynecologic malignancies, Vol. 31. Elsevier; 2004. p. 22–26.

  4. Trimbosand J, Timmers P. Chemotherapy for early ovarian cancer. Curr Opin Obstet Gynecol. 2004;16:43.

    Article  Google Scholar 

  5. Valencia-Sanchez M, Liu J, Hannon G, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Gene Dev. 2006;20:515.

    Article  PubMed  CAS  Google Scholar 

  6. Esquela-Kerscherand A, Slack F. OncomirsómicroRNAs with a role in cancer. Nat Rev Canc. 2006;6:259.

    Article  Google Scholar 

  7. Calin G, Sevignani C, Dumitru C, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci. 2004;101:2999.

    Article  PubMed  CAS  Google Scholar 

  8. Zhang L, Huang J, Yang N, Greshock J, Megraw M, Giannakakis A, et al. microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci. 2006;103:9136.

    Article  PubMed  CAS  Google Scholar 

  9. Lu L, Katsaros D, Rigault de la Longrais I, Sochirca O, Yu H. Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis. Canc Res. 2007;67:10117.

    Article  CAS  Google Scholar 

  10. Dahiya N, Sherman-Baust C, Wang T, Davidson B, Shih I, Zhang Y, et al. MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PLos One. 2008;3.

  11. Friedman J, Liang G, Liu C, Wolff E, Tsai Y, Ye W, et al. The Putative Tumor Suppressor microRNA-101 Modulates the Cancer Epigenome by Repressing the Polycomb Group Protein EZH2. Canc Res. 2009;69:2623.

    Article  CAS  Google Scholar 

  12. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008;322:1695–9.

    Article  PubMed  CAS  Google Scholar 

  13. Malpica A, Deavers M, Lu K, Bodurka D, Atkinson E, Gershenson D, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28:496.

    Article  PubMed  Google Scholar 

  14. Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol. 2006;24:268–73.

    Article  PubMed  CAS  Google Scholar 

  15. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA. 2003;100:11606–11.

    Article  PubMed  CAS  Google Scholar 

  16. Raman JD, Mongan NP, Tickoo SK, Boorjian SA, Scherr DS, Gudas LJ, et al. Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Canc Res. 2005;11:8570–6.

    Article  CAS  Google Scholar 

  17. Varambally S, Dhanasekaran S, Zhou M, Barrette T, Kumar-Sinha C, Sanda M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–9.

    Article  PubMed  CAS  Google Scholar 

  18. Krek A, Grün D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37:495–500.

    Article  PubMed  CAS  Google Scholar 

  19. Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447:425–32.

    Article  PubMed  CAS  Google Scholar 

  20. Wan M, Zweizig S, D’ablaing G, Zheng J, Velicescu M, Dubeau L. Three distinct regions of chromosome 6 are targets of loss of heterozygosity in human ovarian carcinomas. Int J Oncol. 1994;5:1043–8.

    PubMed  CAS  Google Scholar 

  21. el-Deiry WS, Harper JW, O’Connor PM, Velculescu VE, Canman CE, Jackman J, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Canc Res. 1994;54:1169–74.

    CAS  Google Scholar 

  22. Bandres E, Agirre X, Ramirez N, Zarate R, Garcia-Foncillas J. MicroRNAs as cancer players: potential clinical and biological effects. DNA Cell Biol. 2007;26:273–82.

    Article  PubMed  CAS  Google Scholar 

  23. Cumminsand J, Velculescu V. Implications of micro-RNA profiling for cancer diagnosis. Oncogene. 2006;25:6220–7.

    Article  Google Scholar 

  24. Zhang B, Pan X, Cobb GP, Anderson TA, Zhang B, Pan X, et al. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12.

    Article  PubMed  CAS  Google Scholar 

  25. Iorio M, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, et al. MicroRNA signatures in human ovarian cancer. Canc Res. 2007;67:8699.

    Article  CAS  Google Scholar 

  26. Taylorand D, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008;110:13–21.

    Article  Google Scholar 

  27. Yang H, Kong W, He L, Zhao J, O’Donnell J, Wang J, et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Canc Res. 2008;68:425.

    Article  CAS  Google Scholar 

  28. Zhang L, Volinia S, Bonome T, Calin G, Greshock J, Yang N, et al. Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci. 2008;105:7004.

    Article  PubMed  CAS  Google Scholar 

  29. Strillacci A, Griffoni C, Sansone P, Paterini P, Piazzi G, Lazzarini G, et al. MiR-101 downregulation is involved in cyclooxygenase-2 overexpression in human colon cancer cells. Exp Cell Res. 2009;315:1439–47.

    Article  PubMed  CAS  Google Scholar 

  30. Chao-Wei C, Yi H, Ka-Wai L, Lih-Chyang C, Hua-Chien C, Shu-Jen C, et al. PKC alpha mediated induction of miR-101 in human hepatoma HepG2 cells. J Biomed Sci. 2040;17.

  31. Cao Q, Yu J, Dhanasekaran S, Kim J, Mani R, Tomlins S, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008;27:7274–84.

    Article  PubMed  CAS  Google Scholar 

  32. Calinand G, Croce C. MicroRNA signatures in human cancers. Nat Rev Canc. 2006;6:857–66.

    Article  Google Scholar 

  33. Ougolkov A, Bilim V, Billadeau D. Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin Canc Res. 2008;14:6790.

    Article  CAS  Google Scholar 

  34. Haradaand K, Ogden G. An overview of the cell cycle arrest protein, p21WAF1. Oral Oncol. 2000;36:3–7.

    Article  Google Scholar 

  35. Schmider A, Gee C, Friedmann W, Lukas J, Press M, Lichtenegger W, et al. p21 (WAF1/CIP1) protein expression is associated with prolonged survival but not with p53 expression in epithelial ovarian carcinoma. Gynecol Oncol. 2000;77:237–42.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Surgical Oncology & Developmental Therapeutics Department of Surgery, Wayne State University, Detroit, Michigan, 48201, USA

    Assaad Semaan, Aamer M. Qazi, Shelly Seward, Sreedhar Chamala, Christopher P. Steffes, David L. Bouwman, Donald W. Weaver & Ramesh B. Batchu

  2. Department of Ob/Gyn, Wayne State University, Detroit, Michigan, 48201, USA

    Assaad Semaan, Shelly Seward & Robert Morris

  3. MD Anderson Cancer Center Orlando, Gynecologic Oncology, Orlando, Florida, 32806, USA

    Christopher S. Bryant

  4. Division of Gynecologic Surgery, Mayo Clinic Cancer Center, Rochester, Minnesota, 55905, USA

    Sanjeev Kumar

  5. John D. Dingell VA Medical Center, Detroit, Michigan, 48201, USA

    Assaad Semaan, Aamer M. Qazi, Shelly Seward, Sreedhar Chamala, Robert Morris, Christopher P. Steffes, David L. Bouwman, Donald W. Weaver, Scott A. Gruber & Ramesh B. Batchu

  6. Karmanos Cancer Institute, Detroit, Michigan, 48201, USA

    Aamer M. Qazi, Christopher P. Steffes, David L. Bouwman, Donald W. Weaver & Ramesh B. Batchu

  7. Department of Women’s Health Services, Henry Ford Health System, Detroit, Michigan, 48202, USA

    Adnan R Munkarah

  8. Department of Surgery, Wayne State University, John D Dingell VA Medical Center, 4646 John R Rd., Detroit, Michigan, 48201, USA

    Ramesh B. Batchu

Authors
  1. Assaad Semaan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aamer M. Qazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shelly Seward
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sreedhar Chamala
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher S. Bryant
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sanjeev Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christopher P. Steffes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David L. Bouwman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Adnan R Munkarah
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Donald W. Weaver
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Scott A. Gruber
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ramesh B. Batchu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramesh B. Batchu.

Additional information

Assaad Semaan, Aamer M. Qazi, and Shelly Seward are equal contributors to the manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Semaan, A., Qazi, A.M., Seward, S. et al. MicroRNA-101 Inhibits Growth of Epithelial Ovarian Cancer by Relieving Chromatin-Mediated Transcriptional Repression of p21waf1/cip1 . Pharm Res 28, 3079–3090 (2011). https://doi.org/10.1007/s11095-011-0547-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-011-0547-x

KEY WORDS

Search

Navigation