Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

MicroRNA-409 suppresses tumour cell invasion and metastasis by directly targeting radixin in gastric cancers

Oncogene volume 31, pages 4509–4516 (2012)Cite this article

Subjects

Abstract

Emerging evidence has shown that aberrantly expressed microRNAs (miRNAs) are highly associated with tumour development and progression. However, little is known about the potential role of miRNAs in gastric cancer (GC) metastasis. In this study, miR-409-3p was found to be downregulated frequently in human GCs, and its expression was significantly associated with tumor-node-metastasis (TNM) stage and lymph node metastasis. Enforced expression of miR-409 in GC cells significantly reduced their migration and invasion in vitro and their capacity to develop distal pulmonary metastases and peritoneal dissemination in vivo. Moreover, we found that miR-409 exerted its function predominantly through the mature miR-409-3p, but not miR-409-5p. Microarray and bioinformatics analysis identified the pro-metastatic gene radixin (RDX) as a potential miR-409-3p target. Further studies confirmed that miR-409-3p suppressed the expression of RDX by directly binding to its 3′-untranslated region. Silencing of RDX by small interfering RNAs phenocopied the effects of miR-409 overexpression, whereas restoration of RDX in miR-409-overexpressed GC cells reversed the suppressive effects of miR-409. Taken together, these results demonstrate that miR-409 suppresses GC cell invasion and metastasis by directly targeting RDX and that patients with downregulated miR-409-3p are prone to lymph node metastasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

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: 2137–2150.

    Article  Google Scholar 

  2. Hohenberger P, Gretschel S . Gastric cancer. Lancet 2003; 362: 305–315.

    Article  Google Scholar 

  3. Cappetta A, Lonardi S, Pastorelli D, Bergamo F, Lombardi G, Zagonel V . Advanced gastric cancer (GC) and cancer of the gastro-oesophageal junction (GEJ): focus on targeted therapies. Crit Rev Oncol Hematol 2011 (doi:10.1016/j.critrevonc.2010.12.006).

  4. Deng J, Liang H, Sun D, Pan Y . The prognostic analysis of lymph node-positive gastric cancer patients following curative resection. J Surg Res 2010; 161: 47–53.

    Article  Google Scholar 

  5. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 2002; 109: 113–124.

    Article  CAS  Google Scholar 

  6. Oue N, Hamai Y, Mitani Y, Matsumura S, Oshimo Y, Aung PP et al. Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res 2004; 64: 2397–2405.

    Article  CAS  Google Scholar 

  7. Stock M, Otto F . Gene deregulation in gastric cancer. Gene 2005; 360: 1–19.

    Article  CAS  Google Scholar 

  8. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T . Identification of novel genes coding for small expressed RNAs. Science 2001; 294: 853–858.

    Article  CAS  Google Scholar 

  9. Bartel DP . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297.

    Article  CAS  Google Scholar 

  10. Ambros V . The functions of animal microRNAs. Nature 2004; 431: 350–355.

    Article  CAS  Google Scholar 

  11. Calin GA, Croce CM . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–866.

    Article  CAS  Google Scholar 

  12. Kent OA, Mendell JT . A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene 2006; 25: 6188–6196.

    Article  CAS  Google Scholar 

  13. Wang J, Wang Q, Liu H, Hu B, Zhou W, Cheng Y . MicroRNA expression and its implication for the diagnosis and therapeutic strategies of gastric cancer. Cancer Lett 2010; 297: 137–143.

    Article  CAS  Google Scholar 

  14. Wu WK, Lee CW, Cho CH, Fan D, Wu K, Yu J et al. MicroRNA dysregulation in gastric cancer: a new player enters the game. Oncogene 2010; 29: 5761–5771.

    Article  CAS  Google Scholar 

  15. 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.

    Article  Google Scholar 

  16. Takei Y, Takigahira M, Mihara K, Tarumi Y, Yanagihara K . The metastasis-associated microRNA miR-516a-3p is a novel therapeutic target for inhibiting peritoneal dissemination of human scirrhous gastric cancer. Cancer Res 2011; 71: 1442–1453.

    Article  CAS  Google Scholar 

  17. Li Y, Vandenboom II TG, Wang Z, Kong D, Ali S, Philip PA et al. miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res 2010; 70: 1486–1495.

    Article  CAS  Google Scholar 

  18. Liang S, He L, Zhao X, Miao Y, Gu Y, Guo C et al. MicroRNA Let-7f inhibits tumor invasion and metastasis by targeting MYH9 in human gastric cancer. PLoS One 2011; 6: e18409.

    Article  CAS  Google Scholar 

  19. Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S et al. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol 2010; 11: 136–146.

    Article  CAS  Google Scholar 

  20. Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szasz AM, Wang ZC et al. A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 2009; 137: 1032–1046.

    Article  CAS  Google Scholar 

  21. Yu H, Zhang Y, Ye L, Jiang WG . The FERM family proteins in cancer invasion and metastasis. Front Biosci 2011; 16: 1536–1550.

    Article  CAS  Google Scholar 

  22. Doench JG, Sharp PA . Specificity of microRNA target selection in translational repression. Genes Dev 2004; 18: 504–511.

    Article  CAS  Google Scholar 

  23. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 2007; 27: 91–105.

    Article  CAS  Google Scholar 

  24. Kanaan Z, Qadan M, Eichenberger MR, Galandiuk S . The actin-cytoskeleton pathway and its potential role in inflammatory bowel disease-associated human colorectal cancer. Genet Test Mol Biomarkers 2010; 14: 347–353.

    Article  CAS  Google Scholar 

  25. Valastyan S, Chang A, Benaich N, Reinhardt F, Weinberg RA . Concurrent suppression of integrin alpha5, radixin, and RhoA phenocopies the effects of miR-31 on metastasis. Cancer Res 2010; 70: 5147–5154.

    Article  CAS  Google Scholar 

  26. Ding J, Huang S, Wu S, Zhao Y, Liang L, Yan M et al. Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA. Nat Cell Biol 2010; 12: 390–399.

    Article  CAS  Google Scholar 

  27. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 2011; 17: 211–215.

    Article  CAS  Google Scholar 

  28. Chen ZL, Zhao XH, Wang JW, Li BZ, Wang Z, Sun J et al. microRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin. J Biol Chem 2011; 286: 10725–10734.

    Article  CAS  Google Scholar 

  29. 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: 272–286.

    Article  CAS  Google Scholar 

  30. Song YX, Yue ZY, Wang ZN, Xu YY, Luo Y, Xu HM et al. MicroRNA-148b is frequently down-regulated in gastric cancer and acts as a tumor suppressor by inhibiting cell proliferation. Mol Cancer 2011; 10: 1.

    Article  CAS  Google Scholar 

  31. Tsukamoto Y, Nakada C, Noguchi T, Tanigawa M, Nguyen LT, Uchida T et al. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res 2010; 70: 2339–2349.

    Article  CAS  Google Scholar 

  32. Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K . Lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2002; 2: 573–583.

    Article  CAS  Google Scholar 

  33. Tsai KW, Wu CW, Hu LY, Li SC, Liao YL, Lai CH et al. Epigenetic regulation of miR-34b and miR-129 expression in gastric cancer. Int J Cancer 2011; 129: 2600–2610.

    Article  CAS  Google Scholar 

  34. Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q et al. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 2011; 19: 232–243.

    Article  CAS  Google Scholar 

  35. Li X, Zhang Y, Shi Y, Dong G, Liang J, Han Y et al. MicroRNA-107, an oncogene microRNA that regulates tumor invasion and metastasis by targeting DICER1 in gastric cancer: MiR-107 promotes gastric cancer invasion and metastasis. J Cell Mol Med 2011; 15: 1887–1895.

    Article  CAS  Google Scholar 

  36. Hoeflich KP, Ikura M . Radixin: cytoskeletal adopter and signaling protein. Int J Biochem Cell Biol 2004; 36: 2131–2136.

    Article  CAS  Google Scholar 

  37. Arpin M, Chirivino D, Naba A, Zwaenepoel I . Emerging role for ERM proteins in cell adhesion and migration. Cell Adh Migr 2011; 5: 199–206.

    Article  Google Scholar 

  38. Liu G, Voyno-Yasenetskaya TA . Radixin stimulates Rac1 and Ca2+/calmodulin-dependent kinase, CaMKII: cross-talk with Galpha13 signaling. J Biol Chem 2005; 280: 39042–39049.

    Article  CAS  Google Scholar 

  39. Cui Y, Wu J, Zong M, Song G, Jia Q, Jiang J et al. Proteomic profiling in pancreatic cancer with and without lymph node metastasis. Int J Cancer 2009; 124: 1614–1621.

    Article  CAS  Google Scholar 

  40. Ou-Yang M, Liu HR, Zhang Y, Zhu X, Yang Q . ERM stable knockdown by siRNA reduced in vitro migration and invasion of human SGC-7901 cells. Biochimie 2011; 93: 954–961.

    Article  Google Scholar 

Download references

Acknowledgements

We are most grateful for Dr T Didier's gifts of the pWPXL, psPAX2 and pMD2.G lenti-virus plasmids.

Author contributions: BZ, LL, YS, and XH designed the experiments, interpreted the data and wrote the manuscript. BZ, LL, SH, LL, DJ and QT performed experiments. RZ and QW conducted the animal experiments. CW, ZL, YZ, XC and CD collected the human samples and clinical data.

Author information

Author notes

  1. B Zheng and L Liang: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Gastric Cancer and Soft Tissue Sarcomas, Fudan University Shanghai Cancer Center, Shanghai, China

    B Zheng, Q Wang, C Wang, Z Long, Y Zhou, X Cao, C Du, Y Shi & X He

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    B Zheng, Q Wang, C Wang, Z Long, Y Zhou, X Cao, C Du, Y Shi & X He

  3. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    L Liang, S Huang, R Zha, L Liu, D Jia, Q Tian & X He

Authors
  1. B Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Zha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Q Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Q Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Z Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Y Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. X Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Y Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. X He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Y Shi or X He.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zheng, B., Liang, L., Huang, S. et al. MicroRNA-409 suppresses tumour cell invasion and metastasis by directly targeting radixin in gastric cancers. Oncogene 31, 4509–4516 (2012). https://doi.org/10.1038/onc.2011.581

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.581

Keywords

Search

Advanced search

Quick links