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MicroRNA-218 inhibits bladder cancer cell proliferation, migration, and invasion by targeting BMI-1

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Tumor Biology

Abstract

MicroRNAs (miRNAs) are recognized as important molecules and have emerged as important gene regulators in tumorigenesis. Growing evidence suggested that miR-218 was a tumor suppressor in many human cancers. However, its underlying role in bladder cancer (BCa) remains unclear. The aim of this study was to explore the effect of miR-218 on the proliferation, migration, and invasion of BCa cells. We found that miR-218 was frequently downregulated in BCa tissues compared with normal adjacent tissues. In vitro and in vivo assays demonstrated that miR-218 overexpression in the BCa cells inhibited cell proliferation, migration, and invasion. Luciferase reporter assay showed that BMI-1 was a direct target of miR-218. In addition, we found that miR-218 regulated the expression of BMI-1 and its downstream target (PTEN) and participated in the phosphorylation of AKT. Our findings indicate that miR-218 functions as tumor suppressor in BCa, and the miR-218/BMI-1 axis may provide novel diagnostic and therapeutic strategies for the treatment of BCa.

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References

  1. Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009;27(3):289–93. doi:10.1007/s00345-009-0383-3.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Luke C, Tracey E, Stapleton A, Roder D. Exploring contrary trends in bladder cancer incidence, mortality and survival: implications for research and cancer control. Int Med J. 2010;40(5):357–62. doi:10.1111/j.1445-5994.2009.01980.x.

    Article  CAS  Google Scholar 

  3. Lai EC. Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet. 2002;30(4):363–4. doi:10.1038/ng865.

    Article  CAS  PubMed  Google Scholar 

  4. Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–69. doi:10.1038/nrc1840.

    Article  CAS  PubMed  Google Scholar 

  5. Yamasaki T, Seki N, Yoshino H, Itesako T, Hidaka H, Yamada Y, et al. MicroRNA-218 inhibits cell migration and invasion in renal cell carcinoma through targeting caveolin-2 involved in focal adhesion pathway. J Urol. 2013;190(3):1059–68. doi:10.1016/j.juro.2013.02.089.

    Article  CAS  PubMed  Google Scholar 

  6. 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(3):e1000879. doi:10.1371/journal.pgen.1000879.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Alajez NM, Lenarduzzi M, Ito E, Hui AB, Shi W, Bruce J, et al. MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. Cancer Res. 2011;71(6):2381–91. doi:10.1158/0008-5472.can-10-2754.

    Article  CAS  PubMed  Google Scholar 

  8. Tatarano S, Chiyomaru T, Kawakami K, Enokida H, Yoshino H, Hidaka H, et al. miR-218 on the genomic loss region of chromosome 4p15.31 functions as a tumor suppressor in bladder cancer. Int J Oncol. 2011;39(1):13–21. doi:10.3892/ijo.2011.1012.

    CAS  PubMed  Google Scholar 

  9. Yang X, Cheng Y, Li P, Tao J, Deng X, Zhang X, et al. A lentiviral sponge for miRNA-21 diminishes aerobic glycolysis in bladder cancer T24 cells via the PTEN/PI3K/AKT/mTOR axis. Tumour Biol: J Int Soc Oncodev Biol Med. 2014. doi:10.1007/s13277-014-2617-2.

    Google Scholar 

  10. Tu Y, Gao X, Li G, Fu H, Cui D, Liu H, et al. MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res. 2013;73(19):6046–55. doi:10.1158/0008-5472.can-13-0358.

    Article  CAS  PubMed  Google Scholar 

  11. He X, Dong Y, Wu CW, Zhao Z, Ng SS, Chan FK, et al. MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating BMI1 polycomb ring finger oncogene. Mol Med (Cambridge, Mass). 2012;18:1491–8. doi:10.2119/molmed.2012.00304.

    CAS  Google Scholar 

  12. Yoshino H, Seki N, Itesako T, Chiyomaru T, Nakagawa M, Enokida H. Aberrant expression of microRNAs in bladder cancer. Nat Rev Urol. 2013;10(7):396–404. doi:10.1038/nrurol.2013.113.

    Article  CAS  PubMed  Google Scholar 

  13. Nair VS, Maeda LS, Ioannidis JP. Clinical outcome prediction by microRNAs in human cancer: a systematic review. J Natl Cancer Inst. 2012;104(7):528–40. doi:10.1093/jnci/djs027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kou B, Gao Y, Du C, Shi Q, Xu S, Wang CQ, et al. miR-145 inhibits invasion of bladder cancer cells by targeting PAK1. Urol Oncol. 2014;32(6):846–54. doi:10.1016/j.urolonc.2014.01.003.

    Article  CAS  PubMed  Google Scholar 

  15. Lin Y, Chen H, Hu Z, Mao Y, Xu X, Zhu Y, et al. miR-26a inhibits proliferation and motility in bladder cancer by targeting HMGA1. FEBS Lett. 2013;587(15):2467–73. doi:10.1016/j.febslet.2013.06.021.

    Article  CAS  PubMed  Google Scholar 

  16. Uesugi A, Kozaki K, Tsuruta T, Furuta M, Morita K, Imoto I, et al. The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. Cancer Res. 2011;71(17):5765–78. doi:10.1158/0008-5472.CAN-11-0368.

    Article  CAS  PubMed  Google Scholar 

  17. Shi D, Tan Z, Lu R, Yang W, Zhang Y. MicroRNA-218 inhibits the proliferation of human choriocarcinoma JEG-3 cell line by targeting Fbxw8. Biochem Biophys Res Commun. 2014;450(4):1241–6. doi:10.1016/j.bbrc.2014.06.094.

    Article  CAS  PubMed  Google Scholar 

  18. Nishikawa R, Goto Y, Sakamoto S, Chiyomaru T, Enokida H, Kojima S, et al. Tumor-suppressive microRNA-218 inhibits cancer cell migration and invasion via targeting of LASP1 in prostate cancer. Cancer Sci. 2014;105(7):802–11. doi:10.1111/cas.12441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Douglas D, Hsu JH, Hung L, Cooper A, Abdueva D, van Doorninck J, et al. BMI-1 promotes Ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res. 2008;68(16):6507–15. doi:10.1158/0008-5472.CAN-07-6152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kang MK, Kim RH, Kim SJ, Yip FK, Shin KH, Dimri GP, et al. Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival. Br J Cancer. 2007;96(1):126–33. doi:10.1038/sj.bjc.6603529.

    Article  CAS  PubMed  Google Scholar 

  21. Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, et al. The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 2009;119(12):3626–36. doi:10.1172/JCI39374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J, et al. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer. 2011;10:99. doi:10.1186/1476-4598-10-99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liang W, Zhu D, Cui X, Su J, Liu H, Han J, et al. Knockdown BMI1 expression inhibits proliferation and invasion in human bladder cancer T24 cells. Mol Cell Biochem. 2013;382(1–2):283–91. doi:10.1007/s11010-013-1745-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guo BH, Feng Y, Zhang R, Xu LH, Li MZ, Kung HF, et al. Bmi-1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer. Mol Cancer. 2011;10(1):10. doi:10.1186/1476-4598-10-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gong Y, Wang X, Liu J, Shi L, Yin B, Peng X, et al. NSPc1, a mainly nuclear localized protein of novel PcG family members, has a transcription repression activity related to its PKC phosphorylation site at S183. FEBS Lett. 2005;579(1):115–21. doi:10.1016/j.febslet.2004.11.056.

    Article  CAS  PubMed  Google Scholar 

  26. Lu H, Sun HZ, Li H, Cong M. The clinicopathological significance of Bmi-1 expression in pathogenesis and progression of gastric carcinomas. Asian Pac J Cancer Prev: APJCP. 2012;13(7):3437–41.

    Article  PubMed  Google Scholar 

  27. Xu Z, Liu H, Lv X, Liu Y, Li S, Li H. Knockdown of the Bmi-1 oncogene inhibits cell proliferation and induces cell apoptosis and is involved in the decrease of Akt phosphorylation in the human breast carcinoma cell line MCF-7. Oncol Rep. 2011;25(2):409–18. doi:10.3892/or.2010.1078.

    PubMed  Google Scholar 

  28. Li X, Yang Z, Song W, Zhou L, Li Q, Tao K, et al. Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway. Int J Oncol. 2013;43(3):793–802. doi:10.3892/ijo.2013.1992.

    CAS  PubMed  Google Scholar 

  29. Hu J, Liu YL, Piao SL, Yang DD, Yang YM, Cai L. Expression patterns of USP22 and potential targets BMI-1, PTEN, p-AKT in non-small-cell lung cancer. Lung Cancer (Amsterdam, Netherlands). 2012;77(3):593–9. doi:10.1016/j.lungcan.2012.05.112.

    Article  Google Scholar 

  30. Liu B, Wu X, Liu B, Wang C, Liu Y, Zhou Q, et al. MiR-26a enhances metastasis potential of lung cancer cells via AKT pathway by targeting PTEN. Biochim Biophys Acta. 2012;1822(11):1692–704. doi:10.1016/j.bbadis.2012.07.019.

    Article  CAS  PubMed  Google Scholar 

  31. Goschzik T, Gessi M, Denkhaus D, Pietsch T. PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway in papillary tumors of the pineal region. J Neuropathol Exp Neurol. 2014;73(8):747–51. doi:10.1097/NEN.0000000000000093.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Program for Development of Innovative Research Team of the First Affiliated Hospital of Nanjing Medical University, the Provincial Initiative Program for Excellency Disciplines of Jiangsu Province, the National Natural Science Foundation of China (Grant Nos. 81272832 and 81201997), the Natural Science Foundation of Jiangsu Province (Grant No. BK2011848), the Six Major Talent Peak Project of Jiangsu Province (Grant No. 2011-WS-121), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Jiangsu Provincial Special Program of Medical Science (BL2012027). The funders had no role in study design, data collection, and analysis; decision to publish; or preparation of the manuscript.

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    Authors and Affiliations

    1. Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, Jiangsu, 210029, China

      Yidong Cheng, Xiao Yang, Xiaheng Deng, Xiaolei Zhang, Pengchao Li, Jun Tao & Qiang Lu

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    1. Yidong Cheng
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    Correspondence to Qiang Lu.

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    Yidong Cheng, Xiao Yang and Xiaheng Deng contributed equally to this work.

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    Cheng, Y., Yang, X., Deng, X. et al. MicroRNA-218 inhibits bladder cancer cell proliferation, migration, and invasion by targeting BMI-1. Tumor Biol. 36, 8015–8023 (2015). https://doi.org/10.1007/s13277-015-3532-x

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