Advertisement

Tumor Biology

, Volume 33, Issue 5, pp 1589–1597 | Cite as

MicroRNA-181a promotes gastric cancer by negatively regulating tumor suppressor KLF6

  • Xiangyang Zhang
  • Yuqiang Nie
  • Yanlei Du
  • Jie Cao
  • Bo Shen
  • Yuyuang Li
Research Article

Abstract

MicroRNAs have emerged as crucial regulators of tumorigenesis. However, it remains unknown whether miR-181a is involved in the pathogenesis of gastric cancer. In this study, we found that miR-181a is overexpressed in human gastric cancer tissues. Ectopic expression of miR-181a mimic promoted the proliferation, colony formation, migration, and invasion and inhibited the apoptosis of SGC-7901 gastric cancer cells, whereas ectopic expression of miR-181a inhibitor inhibited the malignant phenotypes of SGC-7901 cells. Site-directed mutagenesis and luciferase reporter assay demonstrated that miR-181a repressed KLF6 expression by targeting its 3′-UTR. Western blot analysis further showed that KLF6 protein was significantly decreased or increased when miR-181a mimic or inhibitor was transfected into SGC-7901 cells, respectively. In summary, these data suggest that KLF6 gene is a direct target of miR-181a and miR-181a functions as an oncomir in gastric cancer by repressing the expression of tumor suppressor KLF6.

Keywords

miR-181a Gastric cancer KLF6 Tumor suppressor 

Notes

Acknowledgments

This work was partly supported by the grants from Health bureau of Guangzhou City (No.201102A212011) and from the Natural Science Foundation of Guangdong Province (No.10151006001000016).

Competing interests statement

The authors declare that they have no competing financial interests.

References

  1. 1.
    Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24:2137–50.CrossRefPubMedGoogle Scholar
  2. 2.
    Tamura G. Alterations of tumor suppressor and tumor-related genes in the development and progression of gastric cancer. World J Gastroenterol. 2006;12:192–8.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ushijima T, Sasako M. Focus on gastric cancer. Cancer Cell. 2004;5:121–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  5. 5.
    Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.CrossRefPubMedGoogle Scholar
  6. 6.
    Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, et al. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008;13:272–86.CrossRefPubMedGoogle Scholar
  7. 7.
    Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH, et al. Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res. 2009;37:1672–81.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Galluzzi L, Morselli E, Vitale I, Kepp O, Senovilla L, Criollo A, Servant N, Paccard C, Hupé P, Robert T, Ripoche H, Lazar V, Harel-Bellan A, Dessen P, Barillot E. Kroemer G.miR-181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer Res. 2010;70:1793–803.CrossRefPubMedGoogle Scholar
  9. 9.
    Shin KH, Bae SD, Hong HS, Kim RH, Kang MK. Park NH.miR-181a shows tumor suppressive effect against oral squamous cell carcinoma cells by downregulating K-ras. Biochem Biophys Res Commun. 2011;404:896–902.CrossRefPubMedGoogle Scholar
  10. 10.
    Khella HW, White NM, Faragalla H, Gabril M, Boazak M, Dorian D, Khalil B, Antonios H, Bao TT, Pasic MD, Honey RJ, Stewart R, Pace KT, Bjarnason GA, Jewett MA, Yousef GM. Exploring the role of miRNAs in renal cell carcinoma progression and metastasis through bioinformatic and experimental analyses. Tumor Biol. 2012;33:131–40.CrossRefGoogle Scholar
  11. 11.
    Bieker JJ. Kruppel-like factors: three fingers in many pies. J Biol Chem. 2001;276:34355–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Black AR, Black JD, Azizkhan-Clifford J. Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol. 2001;188:143–60.CrossRefPubMedGoogle Scholar
  13. 13.
    Chen C, Hyytinen ER, Sun X, Helin HJ, Koivisto PA, Frierson Jr HF, et al. Deletion, mutation, and loss of expression of KLF6 in human prostate cancer. Am J Pathol. 2003;162:1349–54.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kremer-Tal S, Reeves HL, Narla G, Thung SN, Schwartz M, Difeo A, et al. Frequent inactivation of the tumor suppressor Kruppel-like factor 6 (KLF6) in hepatocellular carcinoma. Hepatology. 2004;40:1047–52.CrossRefPubMedGoogle Scholar
  15. 15.
    Reeves HL, Narla G, Ogunbiyi O, Haq AI, Katz A, Benzeno S, et al. Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer. Gastroenterology. 2004;126:1090–103.CrossRefPubMedGoogle Scholar
  16. 16.
    Cho YG, Kim CJ, Park CH, Yang YM, Kim SY, Nam SW, et al. Genetic alterations of the KLF6 gene in gastric cancer. Oncogene. 2005;24:4588–90.CrossRefPubMedGoogle Scholar
  17. 17.
    Spinola M, Leoni VP, Galvan A, Korsching E, Conti B, Pastorino U, et al. Genome-wide single nucleotide polymorphism analysis of lung cancer risk detects the KLF6 gene. Cancer Lett. 2007;251:311–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Agell L, Hernandez S, de Muga S, Lorente JA, Juanpere N, Esgueva R, et al. KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations. Mod Pathol. 2008;21:1470–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001;25:402–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Ciafre SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, et al. Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun. 2005;334:1351–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Neilson JR, Zheng GX, Burge CB, Sharp PA. Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev. 2007;21:578–89.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Pearson R, Fleetwood J, Eaton S, Crossley M, Bao S. Kruppel-like transcription factors: a functional family. Int J Biochem Cell Biol. 2008;40:1996–2001.CrossRefPubMedGoogle Scholar
  24. 24.
    Liu L, Liu N, Xu M, Liu Y, Min J, Pang H, Zhang N, Zhang H, Zhang H. Lentivirus-delivered Krüppel-like factor 8 small interfering RNA inhibits gastric cancer cell growth in vitro and in vivo. Tumor Biol. 2012;33:53–61.CrossRefGoogle Scholar
  25. 25.
    Camacho-Vanegas O, Narla G, Teixeira MS, DiFeo A, Misra A, Singh G, et al. Functional inactivation of the KLF6 tumor suppressor gene by loss of heterozygosity and increased alternative splicing in glioblastoma. Int J Cancer. 2007;121:1390–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Song J, Kim CJ, Cho YG, Kim SY, Nam SW, Lee SH, et al. Genetic and epigenetic alterations of the KLF6 gene in hepatocellular carcinoma. J Gastroenterol Hepatol. 2006;21:1286–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Sangodkar J, Shi J, DiFeo A, Schwartz R, Bromberg R, Choudhri A, et al. Functional role of the KLF6 tumour suppressor gene in gastric cancer. Eur J Cancer. 2009;45:666–76.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Narla G, Difeo A, Reeves HL, Schaid DJ, Hirshfeld J, Hod E, et al. A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res. 2005;65:1213–22.CrossRefPubMedGoogle Scholar
  29. 29.
    DiFeo A, Narla G, Hirshfeld J, Camacho-Vanegas O, Narla J, Rose SL, et al. Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination. Clin Cancer Res. 2006;12:3730–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Xiangyang Zhang
    • 1
  • Yuqiang Nie
    • 1
  • Yanlei Du
    • 1
  • Jie Cao
    • 1
  • Bo Shen
    • 1
  • Yuyuang Li
    • 1
  1. 1.Guangzhou Key Laboratory of Digestive Disease, Department of Gastroenterology, First Municipal People’s Hospital of GuangzhouGuangzhou Medical UniversityGuangzhouChina

Personalised recommendations