Tumor Biology

, Volume 36, Issue 9, pp 7143–7149 | Cite as

RETRACTED ARTICLE: MiRNA-494 inhibits metastasis of cervical cancer through Pttg1

  • Bing Chen
  • Zhaohui Hou
  • Chundong Li
  • Ying TongEmail author
Research Article


Many cervical cancer (CC) patients experience early cancer metastasis, resulting in poor therapeutic outcome after resection of primary cancer. Hence, there is a compelling requirement for understanding of the molecular mechanisms underlying the invasiveness control of CC. Pituitary tumor-transforming gene 1 (Pttg1) has been recently reported to promote cancer cell growth and metastasis in a number of various tumors. However, its regulation by microRNAs (miRNAs) as well as its role in CC have not been clarified. Here, we reported significantly higher levels of Pttg1 and significantly lower levels of miR-494 in the resected CC tissue, compared with the adjacent normal cervical tissue from the same patient. Interestingly, Pttg1 levels inversely correlated with miR-494 levels. In vitro, Pttg1 levels determined CC cell invasiveness and were inhibited by miR-494 levels. However, miR-494 levels were not affected by Pttg1 levels. Furthermore, miR-494 inhibited Pttg1 expression in CC cells, through directly binding and inhibition on 3′-UTR of Pttg1 mRNA. Together, our data suggest that Pttg1 may increase CC cell metastasis, which is negatively regulated by miR-494. Our work thus highlights a novel molecular regulatory machinery in metastasis of CC.


Cervical cancer Pituitary tumor-transforming gene 1 miR-494 Cancer metastasis 


Conflicts of interest



  1. 1.
    Kanayama T, Mabuchi S, Fujita M, Kimura T. Calcaneal metastasis in uterine cervical cancer: a case report and a review of the literature. Eur J Gynaecol Oncol. 2012;33:524–5.PubMedGoogle Scholar
  2. 2.
    Setoodeh R, Hakam A, Shan Y. Cerebral metastasis of cervical cancer, report of two cases and review of the literature. Int J Clin Exp Pathol. 2012;5:710–4.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Peters P, Bandi H, Efendy J, Perez-Smith A, Olson S. Rapid growth of cervical cancer metastasis in the brain. J Clin Neurosci. 2010;17:1211–2.CrossRefPubMedGoogle Scholar
  4. 4.
    Chen B, Zhang C, Dong P, Guo Y, Mu N. Molecular regulation of cervical cancer growth and invasion by VEGFA. Tumour Biol. 2014;35:11587–93.CrossRefPubMedGoogle Scholar
  5. 5.
    Yu R, Ren SG, Horwitz GA, Wang Z, Melmed S. Pituitary tumor transforming gene (pttg) regulates placental JEG-3 cell division and survival: evidence from live cell imaging. Mol Endocrinol. 2000;14:1137–46.CrossRefPubMedGoogle Scholar
  6. 6.
    Caporali S, Alvino E, Levati L, Esposito AI, Ciomei M, Brasca MG, et al. Down-regulation of the pttg1 proto-oncogene contributes to the melanoma suppressive effects of the cyclin-dependent kinase inhibitor PHA-848125. Biochem Pharmacol. 2012;84:598–611.CrossRefPubMedGoogle Scholar
  7. 7.
    Vlotides G, Eigler T, Melmed S. Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. Endocr Rev. 2007;28:165–86.CrossRefPubMedGoogle Scholar
  8. 8.
    Tfelt-Hansen J, Kanuparthi D, Chattopadhyay N. The emerging role of pituitary tumor transforming gene in tumorigenesis. Clin Med Res. 2006;4:130–7.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Panguluri SK, Yeakel C, Kakar SS. Pttg: an important target gene for ovarian cancer therapy. J Ovarian Res. 2008;1:6.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    El-Naggar SM, Malik MT, Kakar SS. Small interfering RNA against Pttg: a novel therapy for ovarian cancer. Int J Oncol. 2007;31:137–43.PubMedGoogle Scholar
  11. 11.
    Chen G, Li J, Li F, Li X, Zhou J, Lu Y, et al. Inhibitory effects of anti-sense Pttg on malignant phenotype of human ovarian carcinoma cell line SK-OV-3. J Huazhong Univ Sci Technol Med Sci = Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban = Huazhong keji daxue xuebao Yixue Yingdewen ban. 2004;24:369–72.CrossRefPubMedGoogle Scholar
  12. 12.
    Yan S, Zhou C, Lou X, Xiao Z, Zhu H, Wang Q, et al. Pttg overexpression promotes lymph node metastasis in human esophageal squamous cell carcinoma. Cancer Res. 2009;69:3283–90.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhou C, Liu S, Zhou X, Xue L, Quan L, Lu N, et al. Overexpression of human pituitary tumor transforming gene (hpttg), is regulated by beta-catenin/TCF pathway in human esophageal squamous cell carcinoma. Int J Cancer. 2005;113:891–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Shibata Y, Haruki N, Kuwabara Y, Nishiwaki T, Kato J, Shinoda N, et al. Expression of Pttg (pituitary tumor transforming gene) in esophageal cancer. Jpn J Clin Oncol. 2002;32:233–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhang ML, Lu S, Zheng SS. Epigenetic changes of pituitary tumor-derived transforming gene 1 in pancreatic cancer. Hepatobil Pancreat Dis Int. 2008;7:313–7.Google Scholar
  16. 16.
    Ai J, Zhang Z, Xin D, Zhu H, Yan Q, Xin Z, et al. Identification of over-expressed genes in human renal cell carcinoma by combining suppression subtractive hybridization and cDNA library array. Sci China C Life Sci. 2004;47:148–57.CrossRefPubMedGoogle Scholar
  17. 17.
    Dominguez A, Ramos-Morales F, Romero F, Rios RM, Dreyfus F, Tortolero M, et al. Hpttg, a human homologue of rat Pttg, is overexpressed in hematopoietic neoplasms. Evidence for a transcriptional activation function of hpttg. Oncogene. 1998;17:2187–93.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhou C, Tong Y, Wawrowsky K, Melmed S. Pttg acts as a stat3 target gene for colorectal cancer cell growth and motility. Oncogene. 2014;33:851–61.CrossRefPubMedGoogle Scholar
  19. 19.
    Kim DS, Franklyn JA, Smith VE, Stratford AL, Pemberton HN, Warfield A, et al. Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity. Carcinogenesis. 2007;28:749–59.CrossRefPubMedGoogle Scholar
  20. 20.
    Huang SQ, Liao QJ, Wang XW, Xin DQ, Chen SX, Wu QJ, et al. RNAi-mediated knockdown of pituitary tumor-transforming gene-1 (Pttg1) suppresses the proliferation and invasive potential of PC3 human prostate cancer cells. Braz J Med Biol Res. 2012;45:995–1001.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Huang S, Liao Q, Li L, Xin D. Pttg1 inhibits smad3 in prostate cancer cells to promote their proliferation. Tumour Biol. 2014;35:6265–70.CrossRefPubMedGoogle Scholar
  22. 22.
    Castilla C, Flores ML, Medina R, Perez-Valderrama B, Romero F, Tortolero M, et al. Prostate cancer cell response to paclitaxel is affected by abnormally expressed securin Pttg1. Mol Cancer Ther. 2014;13:2372–83.CrossRefPubMedGoogle Scholar
  23. 23.
    Cao XL, Gao JP, Wang W, Xu Y, Shi HY, Zhang X. Expression of pituitary tumor transforming gene 1 is an independent factor of poor prognosis in localized or locally advanced prostate cancer cases receiving hormone therapy. Asian Pac J Cancer Prev. 2012;13:3083–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Castilla C, Flores ML, Conde JM, Medina R, Torrubia FJ, Japon MA, et al. Downregulation of protein tyrosine phosphatase ptpl1 alters cell cycle and upregulates invasion-related genes in prostate cancer cells. Clin Exp Metastasis. 2012;29:349–58.CrossRefPubMedGoogle Scholar
  25. 25.
    Singh SV, Powolny AA, Stan SD, Xiao D, Arlotti JA, Warin R, et al. Garlic constituent diallyl trisulfide prevents development of poorly differentiated prostate cancer and pulmonary metastasis multiplicity in tramp mice. Cancer Res. 2008;68:9503–11.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bacac M, Provero P, Mayran N, Stehle JC, Fusco C, Stamenkovic I. A mouse stromal response to tumor invasion predicts prostate and breast cancer patient survival. PLoS One. 2006;1:e32.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Crosby ME, Jacobberger J, Gupta D, Macklis RM, Almasan A. E2f4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma. Oncogene. 2007;26:1897–909.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhu X, Mao Z, Na Y, Guo Y, Wang X, Xin D. Significance of pituitary tumor transforming gene 1 (Pttg1) in prostate cancer. Anticancer Res. 2006;26:1253–9.PubMedGoogle Scholar
  29. 29.
    Di Leva G, Croce CM. MiRNA profiling of cancer. Curr Opin Genet Dev. 2013;23:3–11.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Pereira DM, Rodrigues PM, Borralho PM, Rodrigues CM. Delivering the promise of miRNA cancer therapeutics. Drug Discov Today. 2013;18:282–9.CrossRefPubMedGoogle Scholar
  31. 31.
    He W, Li Y, Chen X, Lu L, Tang B, Wang Z, et al. Mir-494 acts as an anti-oncogene in gastric carcinoma by targeting c-myc. J Gastroenterol Hepatol. 2014;29:1427–34.CrossRefPubMedGoogle Scholar
  32. 32.
    Zhou RP, Chen G, Shen ZL, Pan LQ. Cinobufacin suppresses cell proliferation via mir-494 in BGC-823 gastric cancer cells. Asian Pac J Cancer Prev. 2014;15:1241–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Bai Y, Sun Y, Peng J, Liao H, Gao H, Guo Y, et al. Overexpression of secretagogin inhibits cell apoptosis and induces chemoresistance in small cell lung cancer under the regulation of mir-494. Oncotarget. 2014;5:7760–75.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Romano G, Acunzo M, Garofalo M, Di Leva G, Cascione L, Zanca C, et al. Mir-494 is regulated by ERK1/2 and modulates trail-induced apoptosis in non-small-cell lung cancer through bim down-regulation. Proc Natl Acad Sci U S A. 2012;109:16570–5.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Liborio-Kimura TN, Jung HM, Chan EK. Mir-494 represses hoxa10 expression and inhibits cell proliferation in oral cancer. Oral Oncol. 2015;51:151–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Ries J, Vairaktaris E, Agaimy A, Kintopp R, Baran C, Neukam FW, et al. Mir-186, mir-3651 and mir-494: potential biomarkers for oral squamous cell carcinoma extracted from whole blood. Oncol Rep. 2014;31:1429–36.PubMedGoogle Scholar
  37. 37.
    Kwak SY, Yang JS, Kim BY, Bae IH, Han YH. Ionizing radiation-inducible mir-494 promotes glioma cell invasion through EGFR stabilization by targeting p190b RhoGap. Biochim Biophys Acta. 1843;2014:508–16.Google Scholar
  38. 38.
    Asuthkar S, Velpula KK, Nalla AK, Gogineni VR, Gondi CS, Rao JS. Irradiation-induced angiogenesis is associated with an mmp-9-mir-494-syndecan-1 regulatory loop in medulloblastoma cells. Oncogene. 2014;33:1922–33.CrossRefPubMedGoogle Scholar
  39. 39.
    Puck TT, Marcus PI, Cieciura SJ. Clonal growth of mammalian cells in vitro; growth characteristics of colonies from single Hela cells with and without a feeder layer. J Exp Med. 1956;103:273–83.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Liang CC, Park AY, Guan JL. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007;2:329–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Solbach C, Roller M, Peters S, Nicoletti M, Kaufmann M, Knecht R. Pituitary tumor-transforming gene (Pttg): a novel target for anti-tumor therapy. Anticancer Res. 2005;25:121–5.PubMedGoogle Scholar
  42. 42.
    Yamanaka S, Campbell NR, An F, Kuo SC, Potter JJ, Mezey E, et al. Coordinated effects of microRNA-494 induce G(2)/M arrest in human cholangiocarcinoma. Cell Cycle. 2012;11:2729–38.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Bing Chen
    • 1
  • Zhaohui Hou
    • 1
  • Chundong Li
    • 1
  • Ying Tong
    • 1
    Email author
  1. 1.Department of Obstetrics and GynecologyAir Force General Hospital of PLABeijingChina

Personalised recommendations