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-25 promotes gastric cancer migration, invasion and proliferation by directly targeting transducer of ERBB2, 1 and correlates with poor survival

Oncogene volume 34, pages 2556–2565 (2015)Cite this article

Subjects

Abstract

Gastric cancer (GC) is one of the most common tumors and the molecular mechanism underlying its metastasis is still largely unclear. Here, we show that miR-25 was overexpressed in plasma and primary tumor tissues of GC patients with tumor node metastasis stage (III or IV) or lymph node metastasis. MiR-25 inhibition significantly decreased the metastasis, invasion and proliferation of GC cells in vitro, and reduced their capacity to develop distal pulmonary metastases and peritoneal dissemination in vivo. Furthermore, miR-25 repressed transducer of ERBB2, 1 (TOB1) expression by directly binding to TOB1–3′-UTR, and the inverse correlation was observed between the expressions of miR-25 and TOB1 mRNA in primary GC tissues. Moreover, the loss of TOB1 increased the metastasis, invasion and proliferation of GC cells, and the restoration of TOB1 led to suppressed metastasis, invasion and proliferation. The receiver operating characteristics analysis yielded an area under the curve value of 0.7325 in distinguishing the GC patients with death from those with survival. The analysis of optimal cutoff value revealed poor survival in GC patients with high plasma concentrations of miR-25 (>0.2333 amol/μl). Taken together, miR-25 promotes GC progression by directly downregulating TOB1 expression, and may be a noninvasive biomarker for the prognosis of GC patients.

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
Figure 7

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clinicians 2011; 61: 69–90.

    Article  Google Scholar 

  2. Ushijima T, Sasako M . Focus on gastric cancer. Cancer cell 2004; 5: 121–125.

    Article  CAS  Google Scholar 

  3. Zhang C . Novel functions for small RNA molecules. Curr Opin Mol Ther 2009; 11: 641–651.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lujambio A, Lowe SW . The microcosmos of cancer. Nature 2012; 482: 347–355.

    Article  CAS  Google Scholar 

  5. Eulalio A, Mano M, Dal Ferro M, Zentilin L, Sinagra G, Zacchigna S et al. Functional screening identifies miRNAs inducing cardiac regeneration. Nature 2012; 492: 376–381.

    Article  CAS  Google Scholar 

  6. Swarbrick A, Woods SL, Shaw A, Balakrishnan A, Phua Y, Nguyen A et al. miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma. Nat Med 2010; 16: 1134–1140.

    Article  CAS  Google Scholar 

  7. Zhao X, Dou W, He L, Liang S, Tie J, Liu C et al. MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor. Oncogene 2013; 32: 1363–1372.

    Article  CAS  Google Scholar 

  8. Yao Q, Cao Z, Tu C, Zhao Y, Liu H, Zhang S . MicroRNA-146a acts as a metastasis suppressor in gastric cancer by targeting WASF2. Cancer Lett 2013; 335: 219–224.

    Article  CAS  Google Scholar 

  9. Zheng B, Liang L, Huang S, Zha R, Liu L, Jia D et al. MicroRNA-409 suppresses tumour cell invasion and metastasis by directly targeting radixin in gastric cancers. Oncogene 2012; 31: 4509–4516.

    Article  CAS  Google Scholar 

  10. Gao P, Xing AY, Zhou GY, Zhang TG, Zhang JP, Gao C et al. The molecular mechanism of microRNA-145 to suppress invasion-metastasis cascade in gastric cancer. Oncogene 2013; 32: 491–501.

    Article  CAS  Google Scholar 

  11. Kurashige J, Kamohara H, Watanabe M, Hiyoshi Y, Iwatsuki M, Tanaka Y et al. MicroRNA-200b regulates cell proliferation, invasion, and migration by directly targeting ZEB2 in gastric carcinoma. Ann Surg Oncol 2012; 19 (Suppl 3): S656–S664.

    Article  Google Scholar 

  12. Li BS, Zhao YL, Guo G, Li W, Zhu ED, Luo X et al. Plasma microRNAs, miR-223, miR-21 and miR-218, as novel potential biomarkers for gastric cancer detection. PLoS ONE 2012; 7: e41629.

    Article  CAS  Google Scholar 

  13. Kan T, Sato F, Ito T, Matsumura N, David S, Cheng Y et al. The miR-106b-25 Polycistron, Activated by Genomic Amplification, Functions as an Oncogene by Suppressing p21 and Bim. Gastroenterology 2009; 136: 1689–1700.

    Article  CAS  Google Scholar 

  14. Xu X, Chen Z, Zhao X, Wang J, Ding D, Wang Z et al. MicroRNA-25 promotes cell migration and invasion in esophageal squamous cell carcinoma. Biochem Biophys Res Commun 2012; 421: 640–645.

    Article  CAS  Google Scholar 

  15. Kim BH, Hong SW, Kim A, Choi SH, Yoon SO . Prognostic implications for high expression of oncogenic microRNAs in advanced gastric carcinoma. J Surj Oncol 2013; 107: 505–510.

    Article  CAS  Google Scholar 

  16. Akagi T, Kimoto T . Human cell line (HGC-27) derived from the metastatic lymph node of gastric cancer. Acta medica Okayama 1976; 30: 215–219.

    CAS  PubMed  Google Scholar 

  17. 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 

  18. Yu J, Liu P, Cui X, Sui Y, Ji G, Guan R et al. Identification of novel subregions of LOH in gastric cancer and analysis of the HIC1 and TOB1 tumor suppressor genes in these subregions. Mol Cells 2011; 32: 47–55.

    Article  Google Scholar 

  19. Kundu J, Wahab SM, Kundu JK, Choi YL, Erkin OC, Lee HS et al. Tob1 induces apoptosis and inhibits proliferation, migration and invasion of gastric cancer cells by activating Smad4 and inhibiting betacatenin signaling. Int J Oncol 2012; 41: 839–848.

    Article  CAS  Google Scholar 

  20. 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: 1672–1681.

    Article  CAS  Google Scholar 

  21. Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 2005; 438: 685–689.

    Article  Google Scholar 

  22. Wang X, Guo B, Li Q, Peng J, Yang Z, Wang A et al. miR-214 targets ATF4 to inhibit bone formation. Nat Med 2013; 19: 93–100.

    Article  Google Scholar 

  23. Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci USA 2010; 107: 264–269.

    Article  CAS  Google Scholar 

  24. Wahlquist C, Jeong D, Rojas-Munoz A, Kho C, Lee A, Mitsuyama S et al. Inhibition of miR-25 improves cardiac contractility in the failing heart. Nature 2014; 508: 531–535.

    Article  CAS  Google Scholar 

  25. Razumilava N, Bronk SF, Smoot RL, Fingas CD, Werneburg NW, Roberts LR et al. miR-25 targets TNF-related apoptosis inducing ligand (TRAIL) death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma. Hepatology 2012; 55: 465–475.

    Article  CAS  Google Scholar 

  26. Brett JO, Renault VM, Rafalski VA, Webb AE, Brunet A . The microRNA cluster miR-106b~25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiation. Aging 2011; 3: 108–124.

    Article  CAS  Google Scholar 

  27. Li Q, Zou C, Zou C, Han Z, Xiao H, Wei H et al. MicroRNA-25 functions as a potential tumor suppressor in colon cancer by targeting Smad7. Cancer Lett 2013; 335: 168–174.

    Article  CAS  Google Scholar 

  28. Esposito F, Tornincasa M, Pallante P, Federico A, Borbone E, Pierantoni GM et al. Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2. J Clin Endocrinol Metab 2012; 97: E710–E718.

    Article  CAS  Google Scholar 

  29. Zhao H, Wang Y, Yang L, Jiang R, Li W . miR-25 promotes gastric cancer cells growth and motility by targeting RECK. Mol Cell Biochem 2013; 385: 207–213.

    Article  Google Scholar 

  30. Jiao Y, Sun KK, Zhao L, Xu JY, Wang LL, Fan SJ . Suppression of human lung cancer cell proliferation and metastasis in vitro by the transducer of ErbB-2.1 (TOB1). Acta Pharmacol Sin 2012; 33: 250–260.

    Article  CAS  Google Scholar 

  31. Matsuda S, Kawamura-Tsuzuku J, Ohsugi M, Yoshida M, Emi M, Nakamura Y et al. Tob, a novel protein that interacts with p185erbB2, is associated with anti-proliferative activity. Oncogene 1996; 12: 705–713.

    CAS  PubMed  Google Scholar 

  32. Iwanaga K, Sueoka N, Sato A, Sakuragi T, Sakao Y, Tominaga M et al. Alteration of expression or phosphorylation status of tob, a novel tumor suppressor gene product, is an early event in lung cancer. Cancer Lett 2003; 202: 71–79.

    Article  CAS  Google Scholar 

  33. Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N et al. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 2000; 103: 1085–1097.

    Article  CAS  Google Scholar 

  34. Yoshida Y, von Bubnoff A, Ikematsu N, Blitz IL, Tsuzuku JK, Yoshida EH et al. Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mech Dev 2003; 120: 629–637.

    Article  CAS  Google Scholar 

  35. Xiong B, Rui Y, Zhang M, Shi K, Jia S, Tian T et al. Tob1 controls dorsal development of zebrafish embryos by antagonizing maternal beta-catenin transcriptional activity. Dev Cell 2006; 11: 225–238.

    Article  CAS  Google Scholar 

  36. Ezzeddine N, Chang TC, Zhu W, Yamashita A, Chen CY, Zhong Z et al. Human TOB, an antiproliferative transcription factor, is a poly(A)-binding protein-dependent positive regulator of cytoplasmic mRNA deadenylation. Mol Cell Biol 2007; 27: 7791–7801.

    Article  CAS  Google Scholar 

  37. Helms MW, Kemming D, Contag CH, Pospisil H, Bartkowiak K, Wang A et al. TOB1 is regulated by EGF-dependent HER2 and EGFR signaling, is highly phosphorylated, and indicates poor prognosis in node-negative breast cancer. Cancer Res2009; 69: 5049–5056.

    CAS  Google Scholar 

  38. Scapoli L, Palmieri A, Lo Muzio L, Pezzetti F, Rubini C, Girardi A et al. MicroRNA expression profiling of oral carcinoma identifies new markers of tumor progression. Int J Immunopathol Pharmacol 2010; 23: 1229–1234.

    Article  CAS  Google Scholar 

  39. Leite KR, Tomiyama A, Reis ST, Sousa-Canavez JM, Sanudo A, Camara-Lopes LH et al. MicroRNA expression profiles in the progression of prostate can cer—from high-grade prostate intraepithelial neoplasia to metastasis. Urol Oncol 2013; 31: 796–801.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the staff at National Engineering Research Center of Immunological Products. This work was supported by grants from the National Science Foundation of China (NSFC): grant no.81301729 (to LBS) and 81202310 (to XB).

Author information

Author notes

  1. B-S Li and Q-F Zuo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, PR China

    B-S Li, Q-F Zuo, B Xiao, Y Zhuang, X-H Mao, C Wu, H Zeng, Q-M Zou & G Guo

  2. General Surgery and Center of Minimally Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, PR China

    Y-L Zhao

  3. Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China

    S-M Yang

Authors
  1. B-S Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Q-F Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y-L Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. X-H Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S-M Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Q-M Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Q-M Zou or G Guo.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, BS., Zuo, QF., Zhao, YL. et al. MicroRNA-25 promotes gastric cancer migration, invasion and proliferation by directly targeting transducer of ERBB2, 1 and correlates with poor survival. Oncogene 34, 2556–2565 (2015). https://doi.org/10.1038/onc.2014.214

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.214

This article is cited by

Search

Advanced search

Quick links