Advertisement

Tumor Biology

, Volume 37, Issue 11, pp 15241–15252 | Cite as

MicroRNA-218 inhibits the proliferation, migration, and invasion and promotes apoptosis of gastric cancer cells by targeting LASP1

  • Le-Le Wang
  • Lei Wang
  • Xiao-Ying Wang
  • Di Shang
  • Sheng-Jie Yin
  • Li-Li Sun
  • Hong-Bo JiEmail author
Original Article

Abstract

The present study aims to investigate the effects of microRNA-218 (miR-218) on the proliferation, migration, invasion, and apoptosis of gastric cancer (GC) cells by targeting LIM and SH3 domain protein 1 (LASP1). The GC cells in the logarithmic phase were selected and divided into five groups: the blank group, negative control (NC) group, miR-218 inhibitors group, miR-218 inhibitors + siLASP1 group, and miR-218 mimics + siLASP1 group. The miR-218 expression in each group was also detected by qRT-PCR. The CCK8 assay, Transwell migration, and invasion assays and flow cytometry were performed to determine the effects of miR-218 on cell proliferation, migration, invasion, and apoptosis of GC cells. Western blotting was conducted to measure LASP1 protein expression in GC cells after transfection. The qRT-PCR revealed that the transfection of miR-218 mimics could upregulate the miR-218 expression, and the transfection of miR-218 inhibitors could downregulate the miR-218 expression in the GC cells. Compared with the blank and NC groups, the proliferation, migration, and invasion of GC cells were significantly reduced in the miR-218 mimics, miR-218 inhibitors + siLASP1, and miR-218 mimics + siLASP1 groups but enhanced in the miR-218 inhibitors group. Similarly, compared with the blank and NC groups, the cell apoptosis rates in the miR-218 mimics, miR-218 inhibitors + siLASP1, and the miR-218 mimics + siLASP1 groups were significantly increased, while the miR-218 inhibitors group had a lower apoptosis rate. In conclusion, these results indicate that miR-218 could inhibit the proliferation, migration, and invasion and promote apoptosis of GC cells by downregulating LASP1 expression.

Keywords

Gastric cancer MicroRNA-218 LASP1 Proliferation Migration Invasion Apoptosis 

Notes

Acknowledgments

We would like to sincerely give our great attitude to the reviewers for their constructive comments.

Compliance with ethical standards

Ethical approval

This study was approved by the Ethical Committee of Chifeng Hospital. Written informed consents were obtained from all study subjects.

Conflicts of interest

None.

References

  1. 1.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of her2-positive advanced gastric or gastro-oesophageal junction cancer (toga): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.CrossRefPubMedGoogle Scholar
  2. 2.
    Wang K, Liang Q, Li X, Tsoi H, Zhang J, Wang H, et al. Mdga2 is a novel tumour suppressor cooperating with dmap1 in gastric cancer and is associated with disease outcome. Gut. 2015 ;65(10):1619–31.Google Scholar
  3. 3.
    Piazuelo MB, Correa P. Gastric cancer: overview. Colomb Med (Cali). 2013;44(3):192–201.Google Scholar
  4. 4.
    Chiurillo MA. Role of gene polymorphisms in gastric cancer and its precursor lesions: current knowledge and perspectives in Latin American countries. World J Gastroenterol. 2014;20(16):4503–15.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Corso G, Velho S, Paredes J, Pedrazzani C, Martins D, Milanezi F, et al. Oncogenic mutations in gastric cancer with microsatellite instability. Eur J Cancer. 2011;47(3):443–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Miska EA. How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev. 2005;15(5):563–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Li BS, Liu H, Yang WL. Reduced miRNA-218 expression in pancreatic cancer patients as a predictor of poor prognosis. Genet Mol Res. 2015;14(4):16372–8.CrossRefPubMedGoogle Scholar
  9. 9.
    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.PubMedGoogle Scholar
  10. 10.
    Wu DW, Cheng YW, Wang J, Chen CY, Lee H. Paxillin predicts survival and relapse in non-small cell lung cancer by microRNA-218 targeting. Cancer Res. 2010;70(24):10392–401.CrossRefPubMedGoogle Scholar
  11. 11.
    Song L, Huang Q, Chen K, Liu L, Lin C, Dai T, et al. Mir-218 inhibits the invasive ability of glioma cells by direct downregulation of ikk-beta. Biochem Biophys Res Commun. 2010;402(1):135–40.CrossRefPubMedGoogle Scholar
  12. 12.
    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. 2012;18:1491–8.PubMedCentralGoogle Scholar
  13. 13.
    Zhao T, Ren H, Li J, Chen J, Zhang H, Xin W, et al. Lasp1 is a hif1alpha target gene critical for metastasis of pancreatic cancer. Cancer Res. 2015;75(1):111–9.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    Kim M, Kim JH, Baek SJ, Kim SY, Kim YS. Specific expression and methylation of SLIT1, SLIT2, SLIT3, and miR-218 in gastric cancer subtypes. Int J Oncol. 2016;48(6):2497–507.PubMedGoogle Scholar
  16. 16.
    Jiang Z, Song Q, Zeng R, Li J, Li J, Lin X, et al. MicroRNA-218 inhibits EMT, migration and invasion by targeting SFMBT1 and DCUN1D1 in cervical cancer. Oncotarget. 2016 doi: 10.18632/oncotarget.9850
  17. 17.
    Zhang S, Hong Z, Li Q, Lei J, Huang H, Liu Q. Effect of microRNA-218 on the viability, apoptosis and invasion of renal cell carcinoma cells under hypoxia by targeted downregulation of CXCR7 expression. Biomed Pharmacother. 2016;80:213–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Liu B, Tian Y, Li F, Zhao Z, Jiang X, Zhai C, et al. Tumor-suppressing roles of miR-214 and miR-218 in breast cancer. Oncol Rep. 2016;35(6):3178–84.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Zhu K, Ding H, Wang W, Liao Z, Fu Z, Hong Y, et al. Tumor-suppressive miR-218-5p inhibits cancer cell proliferation and migration via EGFR in non-small cell lung cancer. Oncotarget. 2016 ;7(19):28075–85.Google Scholar
  20. 20.
    Gu JJ, Gao GZ, Zhang SM. miR-218 inhibits the tumorigenesis and proliferation of glioma cells by targeting Robo1. Cancer Biomark. 2016;16(3):309–17.CrossRefPubMedGoogle Scholar
  21. 21.
    Chiyomaru T, Enokida H, Kawakami K, Tatarano S, Uchida Y, Kawahara K, et al. Functional role of LASP1 in cell viability and its regulation by microRNAs in bladder cancer. Urol Oncol. 2012;30(4):434–43.CrossRefPubMedGoogle Scholar
  22. 22.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Rice TW, Rusch VW, Ishwaran H, Blackstone EH. Worldwide esophageal cancer C. Cancer of the esophagus and esophagogastric junction: data-driven staging for the seventh edition of the american joint committee on cancer/international union against cancer cancer staging manuals. Cancer. 2010;116(16):3763–73.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59(22):5830–5.PubMedGoogle Scholar
  25. 25.
    Davidson MR, Larsen JE, Yang IA, Hayward NK, Clarke BE, Duhig EE, et al. MicroRNA-218 is deleted and downregulated in lung squamous cell carcinoma. PLoS One. 2010;5(9):e12560.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Li F, Gu C, Tian F, Jia Z, Meng Z, Ding Y, et al. Mir-218 impedes il-6-induced prostate cancer cell proliferation and invasion via suppression of lgr4 expression. Oncol Rep. 2016;35(5):2859–65.PubMedGoogle Scholar
  27. 27.
    Liu Y, Yan W, Zhang W, Chen L, You G, Bao Z, et al. Mir-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor lef1. Oncol Rep. 2012;28(3):1013–21.PubMedGoogle Scholar
  28. 28.
    Zhang JM, Sun CY, Yu SZ, Wang Q, An TL, Li YY, et al. [Relationship between mir-218 and cdk6 expression and their biological impact on glioma cell proliferation and apoptosis]. Zhonghua Bing Li Xue Za Zhi. 2011;40(7):454–9.PubMedGoogle Scholar
  29. 29.
    Xia H, Yan Y, Hu M, Wang Y, Wang Y, Dai Y, et al. Mir-218 sensitizes glioma cells to apoptosis and inhibits tumorigenicity by regulating ecop-mediated suppression of nf-kappab activity. Neuro-Oncology. 2013;15(4):413–22.CrossRefPubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Xin SY, Feng XS, Zhou LQ, Sun JJ, Gao XL, Yao GL. Reduced expression of circulating microRNA-218 in gastric cancer and correlation with tumor invasion and prognosis. World J Gastroenterol. 2014;20(22):6906–11.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Du YY, Zhao LM, Chen L, Sang MX, Li J, Ma M, et al. The tumor-suppressive function of mir-1 by targeting lasp1 and tagln2 in esophageal squamous cell carcinoma. J Gastroenterol Hepatol. 2016;31(2):384–93.CrossRefPubMedGoogle Scholar
  33. 33.
    Hailer A, Grunewald TG, Orth M, Reiss C, Kneitz B, Spahn M, et al. Loss of tumor suppressor mir-203 mediates overexpression of lim and sh3 protein 1 (lasp1) in high-risk prostate cancer thereby increasing cell proliferation and migration. Oncotarget. 2014;5(12):4144–53.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mori M, Nakagami H, Koibuchi N, Miura K, Takami Y, Koriyama H, et al. Zyxin mediates actin fiber reorganization in epithelial-mesenchymal transition and contributes to endocardial morphogenesis. Mol Biol Cell. 2009;20(13):3115–24.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Mise N, Savai R, Yu H, Schwarz J, Kaminski N, Eickelberg O. Zyxin is a transforming growth factor-beta (tgf-beta)/smad3 target gene that regulates lung cancer cell motility via integrin alpha5beta1. J Biol Chem. 2012;287(37):31393–405.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Le-Le Wang
    • 1
  • Lei Wang
    • 1
  • Xiao-Ying Wang
    • 1
  • Di Shang
    • 1
  • Sheng-Jie Yin
    • 1
  • Li-Li Sun
    • 1
  • Hong-Bo Ji
    • 1
    Email author
  1. 1.Medical Ward I of Department of OncologyChifeng HospitalChifengPeople’s Republic of China

Personalised recommendations