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miR-200a Overexpression in Advanced Ovarian Carcinomas as a Prognostic Indicator

  • Zhu, Cheng-Liang (Department of Clinical Laboratory, Renmin Hospital of Wuhan University) ;
  • Gao, Guo-Sheng (Department of Clinical Laboratory, Ningbo NO.2 hospital)
  • Published : 2014.11.06

Abstract

Background: miR-200a expression is frequently altered in numerous cancers. The aim of the present study was to determine the role of microRNA-200a in advanced ovarian carcinomas. Materials and Methods: We measured miR-200a expression in 72 matched normal ovarian tissues and advanced ovarian carcinomas, and also two ovarian carcinoma cell lines (SKOV3 and SKOV3.ip1 - the latter being more invasive and metastatic than the parental SKOV3) by stem-loop real-time RT-PCR based on TaqMan microRNA assay using U6 as a reference. Levels of miR-200a expression were compared by disease stage, tumor grade, histology, and lymph node involvement. To evaluate the role of microRNA-200a, cell proliferation and invasion of SKOV-3 and SKOV-3.ip1 were analyzed with miR-200a inhibitor/mimic transfected cells. Results: Of 72 paired samples, 65 cancer tissues overexpressed microRNA-200a greater than two fold in comparison with matched normal epithelium. Specifically, patients with lymph node metastasis showed significant elevation. The level correlated with clinicopathological features, including high tumor grade, late disease stage, most notably with lymph node metastasis, but not with tumor histology. In addition, SKOV-3.ip1 cells also overexpressed miR-200a compared with SKOV-3, and miR-200a inhibitor transfected SKOV-3.ip1 cells showed significant reduction in cellular proliferation and invasion, while a miR-200a mimic stimulated the opposite behavior. Conclusions: We provide definitive evidence that miR-200a is up-regulated in a significant proportion of advanced ovarian carcinomas, and that elevated miR-200a expression facilitates tumor progression. Our findings support the notion that miR-200a is an onco-microRNA for ovarian cancer, and elevation is a useful potential diagnostic indicator. This study also provides a solid basis for further functional analysis of miR-200a in advanced ovarian cancer.

Keywords

miR-200a;ovarian carcinoma;lymph node metastasis;overexpression;prognostic indicator

References

  1. Calin GA and Croce CM (2006). MicroRNA signatures in human cancers. Nat Rev Cancer, 6, 857-66. https://doi.org/10.1038/nrc1997
  2. Chen J, Wang L, Matyunina LV, et al (2011). Overexpression of miR-429 induces mesenchymal-to-epithelial transition (MET) in metastatic ovarian cancer cells. Gynecol Oncol, 121, 200-5. https://doi.org/10.1016/j.ygyno.2010.12.339
  3. Chen Y, Zhang L and Hao Q (2013). Candidate microRNA biomarkers in human epithelial ovarian cancer: systematic review profiling studies and experimental validation. Cancer Cell Int, 13, 86. https://doi.org/10.1186/1475-2867-13-86
  4. Di Leva G and Croce CM (2013). The role of microRNAs in the tumorigenesis of ovarian cancer. Front Oncol, 3, 153.
  5. Faragalla H, Youssef YM, Scorilas A, et al (2012). The clinical utility of miR-21 as a diagnostic and prognostic marker for renal cell carcinoma. J Mol Diagn, 14, 385-92. https://doi.org/10.1016/j.jmoldx.2012.02.003
  6. Flavin RJ, Smyth PC, Finn SP, et al (2008). Altered eIF6 and Dicer expression is associated with clinicopathological features in ovarian serous carcinoma patients. Mod Pathol, 21, 676-84. https://doi.org/10.1038/modpathol.2008.33
  7. He L, Hannon GJ (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet, 5, 522-31. https://doi.org/10.1038/nrg1379
  8. Bendoraite A, Knouf EC, Garg KS, et al (2010). Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-toepithelial transition. Gynecol Oncol, 116, 117-25. https://doi.org/10.1016/j.ygyno.2009.08.009
  9. Hernando E (2007). microRNAs and cancer: role in tumorigenesis, patient classification and therapy. Clin Transl Oncol, 9, 155-60. https://doi.org/10.1007/s12094-007-0029-0
  10. Hu X, Macdonald DM, Huettner PC, et al (2009). A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer. Gynecol Oncol, 114, 457-64. https://doi.org/10.1016/j.ygyno.2009.05.022
  11. Iorio MV, Visone R, Di Leva G, et al (2007). MicroRNA signatures in human ovarian cancer. Cancer Res, 67, 8699-707. https://doi.org/10.1158/0008-5472.CAN-07-1936
  12. Calin GA, Ferracin M, Cimmino A, et al (2005). A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med, 353, 1793-801. https://doi.org/10.1056/NEJMoa050995
  13. Koberle V, Kronenberger B, Pleli T, et al (2013). Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur J Cancer, 49, 3442-9. https://doi.org/10.1016/j.ejca.2013.06.002
  14. Korpal M, Lee ES, Hu G and Kang Y (2008). The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem, 283, 14910-4. https://doi.org/10.1074/jbc.C800074200
  15. Kota J, Chivukula RR, O'Donnell KA, et al (2009). Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell, 137, 1005-17. https://doi.org/10.1016/j.cell.2009.04.021
  16. Kumar MS, Erkeland SJ, Pester RE, et al (2008). Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA, 105, 3903-8. https://doi.org/10.1073/pnas.0712321105
  17. Laios A, O'Toole S, Flavin R, et al (2008). Potential role of miR-9 and miR-223 in recurrent ovarian cancer. Mol Cancer, 7, 35. https://doi.org/10.1186/1476-4598-7-35
  18. Lu J, Getz G, Miska EA, et al (2005). MicroRNA expression profiles classify human cancers. Nature, 435, 834-8. https://doi.org/10.1038/nature03702
  19. Landen CN, Jr., Birrer MJ and Sood AK (2008). Early events in the pathogenesis of epithelial ovarian cancer. J Clin Oncol, 26, 995-1005. https://doi.org/10.1200/JCO.2006.07.9970
  20. Leskela S, Leandro-Garcia LJ, Mendiola M, et al (2011). The miR-200 family controls beta-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients. Endocr Relat Cancer, 18, 85-95.
  21. Li Z, Lu J, Sun M, et al (2008). Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA, 105, 15535-40. https://doi.org/10.1073/pnas.0808266105
  22. Mateescu B, Batista L, Cardon M, et al (2011). miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med, 17, 1627-35. https://doi.org/10.1038/nm.2512
  23. Mo MH, Chen L, Fu Y, et al (2012). Cell-free circulating miRNA biomarkers in cancer. J Cancer, 3, 432-48. https://doi.org/10.7150/jca.4919
  24. Mostert B, Sieuwerts AM, Martens JW and Sleijfer S (2011). Diagnostic applications of cell-free and circulating tumor cell-associated miRNAs in cancer patients. Expert Rev Mol Diagn, 11, 259-75.
  25. Nam EJ, Yoon H, Kim SW, et al (2008). MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res, 14, 2690-5. https://doi.org/10.1158/1078-0432.CCR-07-1731
  26. Resnick KE, Alder H, Hagan JP, et al (2009). The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol Oncol, 112, 55-9. https://doi.org/10.1016/j.ygyno.2008.08.036
  27. Shell S, Park SM, Radjabi AR, et al (2007). Let-7 expression defines two differentiation stages of cancer. Proc Natl Acad Sci USA, 104, 11400-5. https://doi.org/10.1073/pnas.0704372104
  28. Tavazoie SF, Alarcon C, Oskarsson T, et al (2008). Endogenous human microRNAs that suppress breast cancer metastasis. Nature, 451, 147-52. https://doi.org/10.1038/nature06487
  29. Shen J, Ambrosone CB, DiCioccio RA, et al (2008). A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis. Carcinogenesis, 29, 1963-6. https://doi.org/10.1093/carcin/bgn172
  30. Skaftnesmo KO, Prestegarden L, Micklem DR and Lorens JB (2007). MicroRNAs in tumorigenesis. Curr Pharm Biotechnol, 8, 320-5. https://doi.org/10.2174/138920107783018390
  31. Tang Z, Ow GS, Thiery JP, et al (2013). Meta-analysis of transcriptome reveals let-7b as an unfavorable prognostic biomarker and predicts molecular and clinical subclasses in high-grade serous ovarian carcinoma. Int J Cancer, 134, 306-18.
  32. Taylor DD, Gercel-Taylor C (2008). MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol, 110, 13-21. https://doi.org/10.1016/j.ygyno.2008.04.033
  33. Trang P, Medina PP, Wiggins JF, et al (2010). Regression of murine lung tumors by the let-7 microRNA. Oncogene, 29, 1580-7. https://doi.org/10.1038/onc.2009.445
  34. Wong AS and Auersperg N (2003). Ovarian surface epithelium: family history and early events in ovarian cancer. Reprod Biol Endocrinol, 1, 70. https://doi.org/10.1186/1477-7827-1-70
  35. Yan LX, Huang XF, Shao Q, et al (2008). MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA, 14, 2348-60. https://doi.org/10.1261/rna.1034808
  36. Yanaihara N, Caplen N, Bowman E, et al (2006). Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell, 9, 189-98. https://doi.org/10.1016/j.ccr.2006.01.025
  37. Yang H, Kong W, He L, et al (2008). MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res, 68, 425-33. https://doi.org/10.1158/0008-5472.CAN-07-2488
  38. Yang N, Kaur S, Volinia S, et al (2008). MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res, 68, 10307-14. https://doi.org/10.1158/0008-5472.CAN-08-1954
  39. Zhang L, Volinia S, Bonome T, et al (2008). Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci USA, 105, 7004-9. https://doi.org/10.1073/pnas.0801615105

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