Tumor Biology

, Volume 37, Issue 6, pp 8327–8335 | Cite as

miR-204 regulates the EMT by targeting snai1 to suppress the invasion and migration of gastric cancer

  • Zhe Liu
  • Jin Long
  • Ruixia Du
  • Chunlin Ge
  • Kejian Guo
  • Yuanhong XuEmail author
Original Article


miR-204 was found to be downregulated in gastric cancer (GC) tissues, and the effect of miR-204 function on gastric cancer remains as a mystery. Therefore, this study was aimed at investigating the potential role of miR-204 involved in GC progression. Tissues collected from 60 gastric cancer patients were selected as the case group, while the matched normal paracancer tissues as controls. miR-204 expression levels in tissues and GC cells were detected using real-time fluorescent quantitative PCR. Luciferase assay was adopted to validate the interaction between potential gene targets and miR-204. Transwell assay was performed to evaluate the metastasis of GC cells. By building the epithelial-mesenchymal transition (EMT) model in vitro through the addition of transforming growth factor beta 1 (TGF-β1), expressions of miR-204 and snai1 in the EMT model together with their respective effects on EMT were evaluated. miR-204 was significantly downregulated in GC tissues and invasive GC cells (P < 0.05). The over-expression of miR-204 or downregulation of snai1 could significantly inhibit the metastasis and invasion of GC cells both in vitro and in vivo. The upregulated miR-204 expression or inhibited snai1 expression could suppress the EMT process in EMT in vitro models. Our study provided evidence that miR-204 may suppress the metastasis and invasion of GC cells through the regulation of the EMT process by targeting snai1.


miR-204 Snai1 Gastric cancer Invasion Migration EMT 



This work was supported by grants from Liaoning Provincial Department of Education Science Research Project (L2014299), the National Natural Science Foundation of China (81572360), Liaoning Province Science and Technology Plan Project (2011404013–4), and the Shenyang Municipal Science and Technology Project (F12-277-1-73).

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: Cancer J Clin. 2014;64:9–29.CrossRefGoogle Scholar
  2. 2.
    Lin X, Zhao Y, Song WM, Zhang B. Molecular classification and prediction in gastric cancer. Computat Structural Biotechnol J. 2015;13:448–58.CrossRefGoogle Scholar
  3. 3.
    Kanda M, Kodera Y. Recent advances in the molecular diagnostics of gastric cancer. World J Gastroenterol : WJG. 2015;21:9838–52.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Pecqueux M, Fritzmann J, Adamu M, Thorlund K, Kahlert C, Reissfelder C, et al. Free intraperitoneal tumor cells and outcome in gastric cancer patients: a systematic review and meta-analysis. Oncotarget 2015Google Scholar
  5. 5.
    Kosaka T, Davydova J, Ono HA, Akiyama H, Hirai S, Ohno S, et al. Imaging and antitumoral effect of a cyclo-oxygenase 2-specific replicative adenovirus for small metastatic gastric cancer lesions. Anticancer Res. 2015;35:5201–10.PubMedGoogle Scholar
  6. 6.
    Du C, Zhang C, Hassan S, Biswas MH, Balaji KC. Protein kinase d1 suppresses epithelial-to-mesenchymal transition through phosphorylation of snail. Cancer Res. 2010;70:7810–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Choi YJ, Kim N, Chang H, Lee HS, Park SM, Park JH, et al. Helicobacter pylori-induced epithelial-mesenchymal transition, a potential role of gastric cancer initiation and an emergence of stem cells. Carcinogenesis. 2015;36:553–63.CrossRefPubMedGoogle Scholar
  8. 8.
    Liu Z, Li Q, Li K, Chen L, Li W, Hou M, et al. Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells. Oncogene. 2013;32:4203–13.CrossRefPubMedGoogle Scholar
  9. 9.
    Huang J, Xiao D, Li G, Ma J, Chen P, Yuan W, et al. Epha2 promotes epithelial-mesenchymal transition through the wnt/beta-catenin pathway in gastric cancer cells. Oncogene. 2014;33:2737–47.CrossRefPubMedGoogle Scholar
  10. 10.
    Kang MH, Kim JS, Seo JE, Oh SC, Yoo YA. Bmp2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (pi3k)/akt pathway. Exp Cell Res. 2010;316:24–37.CrossRefPubMedGoogle Scholar
  11. 11.
    Guo HM, Zhang XQ, Xu CH, Zou XP. Inhibition of invasion and metastasis of gastric cancer cells through snail targeting artificial microRNA interference. Asian Pacific J Cancer Prevent : APJCP. 2011;12:3433–8.Google Scholar
  12. 12.
    Masuda R, Semba S, Mizuuchi E, Yanagihara K, Yokozaki H. Negative regulation of the tight junction protein tricellulin by snail-induced epithelial-mesenchymal transition in gastric carcinoma cells. Pathobiol : J Immunopathol, Molec Cell Biol. 2010;77:106–13.CrossRefGoogle Scholar
  13. 13.
    Shin NR, Jeong EH, Choi CI, Moon HJ, Kwon CH, Chu IS, et al. Overexpression of snail is associated with lymph node metastasis and poor prognosis in patients with gastric cancer. BMC Cancer. 2012;12:521.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ryu HS, Park do J, Kim HH, Kim WH, Lee HS. Combination of epithelial-mesenchymal transition and cancer stem cell-like phenotypes has independent prognostic value in gastric cancer. Hum Pathol. 2012;43:520–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Huang YK, Yu JC. Circulating microRNAs and long non-coding RNAs in gastric cancer diagnosis: an update and review. World J Gastroenterol : WJG. 2015;21:9863–86.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zhang Z, Liu S, Shi R, Zhao G. Mir-27 promotes human gastric cancer cell metastasis by inducing epithelial-to-mesenchymal transition. Cancer Genet. 2011;204:486–91.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang L, Wang X, Chen P. Mir-204 down regulates sirt1 and reverts sirt1-induced epithelial-mesenchymal transition, anoikis resistance and invasion in gastric cancer cells. BMC Cancer. 2013;13:290.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Edge SB, Compton CC. The american joint committee on cancer: the 7th edition of the ajcc cancer staging manual and the future of tnm. Ann Surg Oncol. 2010;17:1471–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, et al. Mir-218 inhibits invasion and metastasis of gastric cancer by targeting the robo1 receptor. PLoS Genet. 2010;6:e1000879.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wang FE, Zhang C, Maminishkis A, Dong L, Zhi C, Li R, et al. MicroRNA-204/211 alters epithelial physiology. FASEB J : Off Public Fed Am Soc Experiment Biol. 2010;24:1552–71.CrossRefGoogle Scholar
  21. 21.
    Shi Y, Huang J, Zhou J, Liu Y, Fu X, Li Y, et al. MicroRNA-204 inhibits proliferation, migration, invasion and epithelial-mesenchymal transition in osteosarcoma cells via targeting sirtuin 1. Oncol Rep. 2015;34:399–406.PubMedGoogle Scholar
  22. 22.
    Qiu YH, Wei YP, Shen NJ, Wang ZC, Kan T, Yu WL, et al. Mir-204 inhibits epithelial to mesenchymal transition by targeting slug in intrahepatic cholangiocarcinoma cells. Cell Physiol Biochem : Int J Experiment Cell Physiol, Biochem, Pharmacol. 2013;32:1331–41.CrossRefGoogle Scholar
  23. 23.
    Sacconi A, Biagioni F, Canu V, Mori F, Di Benedetto A, Lorenzon L, et al. Mir-204 targets bcl-2 expression and enhances responsiveness of gastric cancer. Cell Death Dis. 2012;3:e423.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wu D, Pan H, Zhou Y, Zhang Z, Qu P, Zhou J, et al. Upregulation of microRNA-204 inhibits cell proliferation, migration and invasion in human renal cell carcinoma cells by downregulating sox4. Molec Med Rep 2015.Google Scholar
  25. 25.
    Shi L, Zhang B, Sun X, Lu S, Liu Z, Liu Y, et al. Mir-204 inhibits human nsclc metastasis through suppression of nuak1. Br J Cancer. 2014;111:2316–27.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Yin Y, Zhang B, Wang W, Fei B, Quan C, Zhang J, et al. Mir-204-5p inhibits proliferation and invasion and enhances chemotherapeutic sensitivity of colorectal cancer cells by downregulating rab22a. Clin Cancer Res : Off J Am Assoc Cancer Res. 2014;20:6187–99.CrossRefGoogle Scholar
  27. 27.
    Chung TK, Lau TS, Cheung TH, Yim SF, Lo KW, Siu NS, et al. Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating foxc1. Int J Cancer J Int du Cancer. 2012;130:1036–45.CrossRefGoogle Scholar
  28. 28.
    Lee Y, Yang X, Huang Y, Fan H, Zhang Q, Wu Y, et al. Network modeling identifies molecular functions targeted by mir-204 to suppress head and neck tumor metastasis. PLoS Comput Biol. 2010;6:e1000730.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Katoh M. Identification and characterization of human snail3 (snai3) gene in silico. Int J Molec Med. 2003;11:383–8.PubMedGoogle Scholar
  30. 30.
    Kaufhold S, Bonavida B. Central role of snail1 in the regulation of emt and resistance in cancer: a target for therapeutic intervention. J Experiment Clin Cancer Res : CR. 2014;33:62.CrossRefGoogle Scholar
  31. 31.
    Zhao F, Wang M, Li S, Bai X, Bi H, Liu Y, et al. Dach1 inhibits snai1-mediated epithelial-mesenchymal transition and represses breast carcinoma metastasis. Oncogenesis. 2015;4:e143.CrossRefPubMedGoogle Scholar
  32. 32.
    Wu W, Ding H, Cao J, Zhang W. Fbxl5 inhibits metastasis of gastric cancer through suppressing snail1. Cell Physiol Biochem : Int J Experiment Cell Physiol, Biochem, Pharmacol. 2015;35:1764–72.CrossRefGoogle Scholar
  33. 33.
    Grande MT, Sanchez-Laorden B, Lopez-Blau C, De Frutos CA, Boutet A, Arevalo M, et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med. 2015;21:989–97.CrossRefPubMedGoogle Scholar
  34. 34.
    Li J, Yu H, Xi M, Ma D, Lu X. The snai1 3′utr functions as a sponge for multiple migration-/invasion-related microRNAs. Tumour Biol : J Int Soc Oncodevelop Biol Med. 2015;36:1067–72.CrossRefGoogle Scholar
  35. 35.
    Horvay K, Jarde T, Casagranda F, Perreau VM, Haigh K, Nefzger CM, et al. Snai1 regulates cell lineage allocation and stem cell maintenance in the mouse intestinal epithelium. EMBO J. 2015;34:1319–35.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Huang N, Wu Z, Lin L, Zhou M, Wang L, Ma H, et al. Mir-338-3p inhibits epithelial-mesenchymal transition in gastric cancer cells by targeting zeb2 and macc1/met/akt signaling. Oncotarget. 2015;6:15222–34.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Yi EY, Park SY, Jung SY, Jang WJ, Kim YJ. Mitochondrial dysfunction induces emt through the tgf-beta/smad/snail signaling pathway in hep3b hepatocellular carcinoma cells. Int J Oncol 2015.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Zhe Liu
    • 1
  • Jin Long
    • 1
  • Ruixia Du
    • 2
  • Chunlin Ge
    • 1
  • Kejian Guo
    • 1
  • Yuanhong Xu
    • 1
    Email author
  1. 1.Department of Pancreatic SurgeryFirst Hospital of China Medical UniversityShenyangChina
  2. 2.Department of Otorhinolaryngology, Fengtian HospitalShenyang Medical UniversityShenyangChina

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