Tumor Biology

, Volume 37, Issue 10, pp 14009–14023 | Cite as

Depletion of Dicer promotes epithelial ovarian cancer progression by elevating PDIA3 expression

  • Ying Zhu
  • Liqiong Cai
  • Jing Guo
  • Na Chen
  • Xiaoqing Yi
  • Yong Zhao
  • Jing Cai
  • Zehua Wang
Original Article


Dicer is an essential component of the microRNA (miRNA) processing machinery whose low expression is associated with advanced stage and poor clinical outcome in epithelial ovarian cancer. To investigate the functional relevance of Dicer in epithelial ovarian cancer and to identify its downstream effectors, two-dimensional gel electrophoresis combined with mass spectrometry was used for proteomic profiling. Dicer depletion promoted ovarian cancer cell proliferation and migration accompanied by a global upregulation of proteins. Twenty-six proteins, 7 upregulated and 19 downregulated, were identified. The functions of the identified proteins and their interactions were bioinformatically analyzed. Among them, protein disulfide-isomerase A3 (PDIA3) was considered to be a potential target protein of Dicer. PDIA3 repression by siRNA could significantly relieve the proliferation- and migration-promoting effect mediated by Dicer depletion in vitro and in vivo. Moreover, the miRNAs targeting PDIA3 were decreased in cells with Dicer depletion. In summary, low Dicer expression contributes to epithelial ovarian cancer progression by elevating PDIA3 expression.


Dicer Ovarian cancer Two-dimensional electrophoresis MicroRNA PDIA3 


Author contributions

Jing Cai and Zehua Wang conceived and designed the research. Ying Zhu and Liqiong Cai performed the experiments and analyzed the data. Na Chen, Xiaoqing Yi, Jing Guo, and Yong Zhao provided administrative and technical support. Ying Zhu wrote the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards


This work was supported by the National Natural Science Foundation of China (Nos. 81502248 and 81572572).

Conflicts of interest


Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committee of the Tongji Medical College, Huazhong University of Science and Technology.


  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Merritt WM, Bar-Eli M, Sood AK. The dicey role of Dicer: implications for RNAi therapy. Cancer Res. 2010;70:2571–4.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hammond SM. An overview of microRNAs. Adv Drug Deliv Rev. 2015;87:3–14.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Wu JF, Shen W, Liu NZ, Zeng GL, Yang M, Zuo GQ, Gan XN, Ren H, Tang KF. Down-regulation of Dicer in hepatocellular carcinoma. Med Oncol. 2011;28:804–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Poursadegh Zonouzi AA, Nejatizadeh A, Rahmati-Yamchi M, Fardmanesh H, Shakerizadeh S, Poursadegh Zonouzi A, Nejati-Koshki K, Shekari M. Dysregulated expression of Dicer in invasive ductal breast carcinoma. Med Oncol. 2015;32:203.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhang J, Zhang XH, Wang CX, Liu B, Fan XS, Wen JJ, Shi QL, Zhou XJ. Dysregulation of microRNA biosynthesis enzyme Dicer plays an important role in gastric cancer progression. Int J Clin Exp Pathol. 2014;7:1702–7.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhao H, Jin X, Su H, Deng X, Fang Y, Shen L, Xie C. Down-regulation of Dicer expression in cervical cancer tissues. Med Oncol. 2014;31:937.CrossRefPubMedGoogle Scholar
  9. 9.
    Pampalakis G, Diamandis EP, Katsaros D, Sotiropoulou G. Down-regulation of Dicer expression in ovarian cancer tissues. Clin Biochem. 2010;43:324–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Merritt WM, Lin YG, Han LY, Kamat AA, Spannuth WA, Schmandt R, Urbauer D, Pennacchio LA, Cheng JF, Nick AM, Deavers MT, Mourad-Zeidan A, Wang H, Mueller P, Lenburg ME, Gray JW, Mok S, Birrer MJ, Lopez-Berestein G, Coleman RL, Bar-Eli M, Sood AK. Dicer, Drosha, and outcomes in patients with ovarian cancer. N Engl J Med. 2008;359:2641–50.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Faggad A, Budczies J, Tchernitsa O, Darb-Esfahani S, Sehouli J, Muller BM, Wirtz R, Chekerov R, Weichert W, Sinn B, Mucha C, Elwali NE, Schafer R, Dietel M, Denkert C. Prognostic significance of dicer expression in ovarian cancer-link to global microRNA changes and oestrogen receptor expression. J Pathol. 2010;220:382–91.PubMedGoogle Scholar
  12. 12.
    Kuang Y, Cai J, Li D, Han Q, Cao J, Wang Z. Repression of Dicer is associated with invasive phenotype and chemoresistance in ovarian cancer. Oncol Lett. 2013;5:1149–54.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Kim J, Coffey DM, Creighton CJ, Yu Z, Hawkins SM, Matzuk MM. High-grade serous ovarian cancer arises from fallopian tube in a mouse model. Proc Natl Acad Sci U S A. 2012;109:3921–6.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hu S, Yu L, Li Z, Shen Y, Wang J, Cai J, Xiao L, Wang Z. Overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells in vitro and in vivo. Cancer Biol Ther. 2010;10:788–95.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhou J, Cai J, Huang Z, Ding H, Wang J, Jia J, Zhao Y, Huang D, Wang Z. Proteomic identification of target proteins following Drosha knockdown in cervical cancer. Oncol Rep. 2013;30:2229–37.PubMedGoogle Scholar
  16. 16.
    Zhao S, Wen Z, Liu S, Liu Y, Li X, Ge Y, Li S. MicroRNA-148a inhibits the proliferation and promotes the paclitaxel-induced apoptosis of ovarian cancer cells by targeting PDIA3. Mol Med Rep. 2015;12:3923–9.PubMedGoogle Scholar
  17. 17.
    Comegna M, Succoio M, Napolitano M, Vitale M, D’Ambrosio C, Scaloni A, Passaro F, Zambrano N, Cimino F, Faraonio R. Identification of mir-494 direct targets involved in senescence of human diploid fibroblasts. FASEB J Off Publ Fed Am Soc Exp Biol. 2014;28:3720–33.Google Scholar
  18. 18.
    Ma X, Fan Y, Gao Y, Zhang Y, Huang Q, Ai Q, Ni D, Chen W, Zhang P, Song E, Wang B, Shi T, Zheng T, Zhang X. Dicer is down-regulated in clear cell renal cell carcinoma and in vitro dicer knockdown enhances malignant phenotype transformation. Urol Oncol. 2014;32:46 e49–17.CrossRefGoogle Scholar
  19. 19.
    Zeng S, Yang J, Zhao J, Liu Q, Rong M, Guo Z, Gao W. Silencing Dicer expression enhances cellular proliferative and invasive capacities in human tongue squamous cell carcinoma. Oncol Rep. 2014;31:867–73.PubMedGoogle Scholar
  20. 20.
    Muller PA, Trinidad AG, Caswell PT, Norman JC, Vousden KH. Mutant p53 regulates Dicer through p63-dependent and -independent mechanisms to promote an invasive phenotype. J Biol Chem. 2014;289:122–32.CrossRefPubMedGoogle Scholar
  21. 21.
    Iliou MS, da Silva-Diz V, Carmona FJ, Ramalho-Carvalho J, Heyn H, Villanueva A, Munoz P, Esteller M. Impaired dicer1 function promotes stemness and metastasis in colon cancer. Oncogene. 2014;33:4003–15.CrossRefPubMedGoogle Scholar
  22. 22.
    Chiosea S, Jelezcova E, Chandran U, Acquafondata M, McHale T, Sobol RW, Dhir R. Up-regulation of Dicer, a component of the microRNA machinery, in prostate adenocarcinoma. Am J Pathol. 2006;169:1812–20.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Muralidhar B, Goldstein LD, Ng G, Winder DM, Palmer RD, Gooding EL, Barbosa-Morais NL, Mukherjee G, Thorne NP, Roberts I, Pett MR, Coleman N. Global microRNA profiles in cervical squamous cell carcinoma depend on Drosha expression levels. J Pathol. 2007;212:368–77.CrossRefPubMedGoogle Scholar
  24. 24.
    Sugito N, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Kurehara H, Ando T, Mori R, Takashima N, Ogawa R, Fujii Y. RNASEN regulates cell proliferation and affects survival in esophageal cancer patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12:7322–8.CrossRefGoogle Scholar
  25. 25.
    Zhang B, Chen H, Zhang L, Dakhova O, Zhang Y, Lewis MT, Creighton CJ, Ittmann MM, Xin L. A dosage-dependent pleiotropic role of dicer in prostate cancer growth and metastasis. Oncogene. 2014;33:3099–108.CrossRefPubMedGoogle Scholar
  26. 26.
    Kurzynska-Kokorniak A, Koralewska N, Pokornowska M, Urbanowicz A, Tworak A, Mickiewicz A, Figlerowicz M. The many faces of Dicer: the complexity of the mechanisms regulating dicer gene expression and enzyme activities. Nucleic Acids Res. 2015;43:4365–80.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Coppari S, Altieri F, Ferraro A, Chichiarelli S, Eufemi M, Turano C. Nuclear localization and DNA interaction of protein disulfide isomerase ERp57 in mammalian cells. J Cell Biochem. 2002;85:325–33.CrossRefPubMedGoogle Scholar
  28. 28.
    Turano C, Gaucci E, Grillo C, Chichiarelli S. ERp57/GRP58: a protein with multiple functions. Cell Mol Biol Lett. 2011;16:539–63.CrossRefPubMedGoogle Scholar
  29. 29.
    Chichiarelli S, Ferraro A, Altieri F, Eufemi M, Coppari S, Grillo C, Arcangeli V, Turano C. The stress protein ERp57/GRP58 binds specific DNA sequences in HeLa cells. J Cell Physiol. 2007;210:343–51.CrossRefPubMedGoogle Scholar
  30. 30.
    Eufemi M, Coppari S, Altieri F, Grillo C, Ferraro A, Turano C. ERp57 is present in STAT3-DNA complexes. Biochem Biophys Res Commun. 2004;323:1306–12.CrossRefPubMedGoogle Scholar
  31. 31.
    Hirano N, Shibasaki F, Sakai R, Tanaka T, Nishida J, Yazaki Y, Takenawa T, Hirai H. Molecular cloning of the human glucose-regulated protein ERp57/GRP58, a thiol-dependent reductase. Identification of its secretory form and inducible expression by the oncogenic transformation. Eur j Biochem FEBS. 1995;234:336–42.CrossRefGoogle Scholar
  32. 32.
    Celli CM, Jaiswal AK. Role of GRP58 in mitomycin c-induced DNA cross-linking. Cancer Res. 2003;63:6016–25.PubMedGoogle Scholar
  33. 33.
    Santana-Codina N, Carretero R, Sanz-Pamplona R, Cabrera T, Guney E, Oliva B, Clezardin P, Olarte OE, Loza-Alvarez P, Mendez-Lucas A, Perales JC, Sierra A. A transcriptome-proteome integrated network identifies endoplasmic reticulum thiol oxidoreductase (ERp57) as a hub that mediates bone metastasis. Mol Cell Proteomics MCP. 2013;12:2111–25.CrossRefPubMedGoogle Scholar
  34. 34.
    Liao CJ, Wu TI, Huang YH, Chang TC, Wang CS, Tsai MM, Lai CH, Liang Y, Jung SM, Lin KH. Glucose-regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer. Cancer Sci. 2011;102:2255–63.CrossRefPubMedGoogle Scholar
  35. 35.
    Cicchillitti L, Di Michele M, Urbani A, Ferlini C, Donat MB, Scambia G, Rotilio D. Comparative proteomic analysis of paclitaxel sensitive A2780 epithelial ovarian cancer cell line and its resistant counterpart A2780tc1 by 2D-DIGE: the role of ERp57. J Proteome Res. 2009;8:1902–12.CrossRefPubMedGoogle Scholar
  36. 36.
    Chichiarelli S, Gaucci E, Ferraro A, Grillo C, Altieri F, Cocchiola R, Arcangeli V, Turano C, Eufemi M. Role of ERp57 in the signaling and transcriptional activity of STAT3 in a melanoma cell line. Arch Biochem Biophys. 2010;494:178–83.CrossRefPubMedGoogle Scholar
  37. 37.
    Liao CJ, Wu TI, Huang YH, Chang TC, Lai CH, Jung SM, Hsueh C, Lin KH. Glucose-regulated protein 58 modulates beta-catenin protein stability in a cervical adenocarcinoma cell line. BMC Cancer. 2014;14:555.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Sansone P, Bromberg J. Targeting the interleukin-6/Jak/stat pathway in human malignancies. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:1005–14.CrossRefGoogle Scholar
  39. 39.
    Anastas JN, Moon RT. Wnt signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13:11–26.CrossRefPubMedGoogle Scholar
  40. 40.
    Tan FH, Putoczki TL, Stylli SS, Luwor RB. The role of STAT3 signaling in mediating tumor resistance to cancer therapy. Curr Drug Targets. 2014;15:1341–53.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.College of Life ScienceWuhan UniversityWuhanChina

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