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

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Tumor Biology

Abstract

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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.

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References

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ushijima T, Sasako M. Focus on gastric cancer. Cancer Cell. 2004;5:121–5.

    Article  CAS  PubMed  Google Scholar 

  4. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

    Article  CAS  PubMed  Google Scholar 

  5. Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  11. Bieker JJ. Kruppel-like factors: three fingers in many pies. J Biol Chem. 2001;276:34355–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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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.

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Authors and Affiliations

  1. Guangzhou Key Laboratory of Digestive Disease, Department of Gastroenterology, First Municipal People’s Hospital of Guangzhou, Guangzhou Medical University, No.1 Panfu Road, Guangzhou, 510180, China

    Xiangyang Zhang, Yuqiang Nie, Yanlei Du, Jie Cao, Bo Shen & Yuyuang Li

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  1. Xiangyang Zhang
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  2. Yuqiang Nie
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Correspondence to Yuqiang Nie.

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Zhang, X., Nie, Y., Du, Y. et al. MicroRNA-181a promotes gastric cancer by negatively regulating tumor suppressor KLF6. Tumor Biol. 33, 1589–1597 (2012). https://doi.org/10.1007/s13277-012-0414-3

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  • DOI: https://doi.org/10.1007/s13277-012-0414-3

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