Skip to main content

Advertisement

SpringerLink
Log in

The miR-506-Induced Epithelial–Mesenchymal Transition is Involved in Poor Prognosis for Patients with Gastric Cancer

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

MicroRNAs have roles in the regulation of the epithelial–mesenchymal transition (EMT). Findings have shown that miR-506 inhibits the expression of SNAI2 and that low expression of miR-506 is associated with poor prognoses in ovarian and breast cancers. This study investigated the role of miR-506 in survival and the EMT in patients with gastric cancer.

Methods

In this study, miR-506 and SNAI2 mRNA levels were measured in 141 cases of gastric cancer by quantitative reverse transcription polymerase chain reaction, and the protein expressions of SNAI2 and E-cadherin in 39 cases were validated by immunohistochemical analysis. Next, the associations between their expression levels and clinicopathologic factors were evaluated. In addition, cell proliferation, migration, and luciferase activity of the 3′ untranslated region (UTR) of SNAI2 were analyzed using pre-miR-506 precursor in two human gastric cancer cell lines.

Results

Low expression of miR-506 was significantly correlated with poor overall survival in both the univariate analysis (P = 0.016) and the multivariate analysis (P < 0.05). Low miR-506 expression was significantly correlated with high SNAI2 expression (P = 0.009) and poorly differentiated type (P = 0.015). In vitro, miR-506 suppressed SNAI2 expression by binding to its 3′UTR, resulting in increased expression of E-cadherin (P < 0.05), verified by immunohistochemical analysis. Pre-miR-506 transfected cells showed significantly suppressed cell proliferation and migration (P < 0.05) compared with the control cells.

Conclusions

The EMT was directly suppressed by miR-506, and its low expression was an independent prognostic factor in gastric cancer patients. The data indicated that miR-506 may act as a tumor suppressor and could be a novel therapeutic agent.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. IARC. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Retrieved 10 January 2014 at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.

  2. Hohenberger P, Gretschel S. Gastic cancer. Lancet. 2003; 362:305–15.

    Article  PubMed  Google Scholar 

  3. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial–mesenchymal transitions in development and disease. Cell. 2009;139:871–90.

    Article  PubMed  CAS  Google Scholar 

  4. Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.

    Article  PubMed  CAS  Google Scholar 

  5. Katoh M. Epithelial–mesenchymal transition in gastric cancer (review). Int J Oncol. 2005;27:1677–83.

    PubMed  CAS  Google Scholar 

  6. Murai T, Yamada S, Fuchs BC, et al. Epithelial-to-mesenchymal transition predicts prognosis in clinical gastric cancer. J Surg Oncol. 2014;109:684–9.

    Article  PubMed  CAS  Google Scholar 

  7. Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. J Am Med Assoc. 2007;297:2360–72.

    Article  CAS  Google Scholar 

  8. Bhayani MK, Calin GA, Lai SY. Functional relevance of miRNA sequences in human disease. Mutat Res. 2012;731:14–9.

    Article  PubMed  CAS  Google Scholar 

  9. Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development. 2005;132:4653–62.

    Article  PubMed  CAS  Google Scholar 

  10. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.

    Article  PubMed  CAS  Google Scholar 

  11. Bouyssou JM, Manier S, Huynh D, Issa S, Roccaro AM, Ghobrial IM. Regulation of microRNAs in cancer metastasis. Biochim Biophys Acta. 2014;1845:255–65.

    PubMed  CAS  PubMed Central  Google Scholar 

  12. Song F, Yang D, Liu B, et al. Integrated microRNA network analyses identify a poor prognosis subtype of gastric cancer characterized by the miR-200 family. Clin Cancer Res. 2014;20:878–89.

    Article  PubMed  CAS  Google Scholar 

  13. Duarte I, Llanos O. Patterns of metastases in intestinal and diffuse types of carcinoma of the stomach. Hum Pathol. 1981;12:237–42.

    Article  PubMed  CAS  Google Scholar 

  14. Maehara Y, Moriguchi S, Kakeji Y, et al. Pertinent risk factors and gastric carcinoma with synchronous peritoneal dissemination or liver metastasis. Surgery. 1991;110:820–3.

    PubMed  CAS  Google Scholar 

  15. Okugawa Y, Inoue Y, Tanaka K, et al. Smad interacting protein 1 (SIP1) is associated with peritoneal carcinomatosis in intestinal type gastric cancer. Clin Exp Metastasis. 2013;30:417–29.

    Article  PubMed  CAS  Google Scholar 

  16. Okugawa Y, Toiyama Y, Tanaka K, et al. Clinical significance of zinc finger E-box binding homeobox 1 (ZEB1) in human gastric cancer. J Surg Oncol. 2012; 106:280–5.

    Article  PubMed  CAS  Google Scholar 

  17. Yang D, Sun Y, Hu L, et al. Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell. 2013;23:186–99.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Arora H, Qureshi R, Park WY. miR-506 regulates epithelial mesenchymal transition in breast cancer cell lines. PloS One. 2013;8:e64273.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mori M, Mimori K, Yoshikawa Y, et al. Analysis of the gene-expression profile regarding the progression of human gastric carcinoma. Surgery. 2002;131:S39–47.

    Article  PubMed  Google Scholar 

  20. Ieta K, Ojima E, Tanaka F, et al. Identification of overexpressed genes in hepatocellular carcinoma, with special reference to ubiquitin-conjugating enzyme E2C gene expression. Int J Cancer. 2007;121:33–8.

    Article  PubMed  CAS  Google Scholar 

  21. Mizuno H, Kitada K, Nakai K, Sarai A. PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med Genomics. 2009;2:18.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Akagawa S, Ohuchida K, Torata N, et al. Peritoneal myofibroblasts at metastatic foci promote dissemination of pancreatic cancer. Int J Oncol. 2014;45:113–20.

    PubMed  CAS  Google Scholar 

  23. Miyake S, Kitajima Y, Nakamura J, et al. HIF-1alpha is a crucial factor in the development of peritoneal dissemination via natural metastatic routes in scirrhous gastric cancer. Int J Oncol. 2013;43:1431–40.

    PubMed  CAS  Google Scholar 

  24. Berx G, Van Roy F. The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res. 2001;3:289–93.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Paredes J, Figueiredo J, Albergaria A, et al. Epithelial E- and P-cadherins: role and clinical significance in cancer. Biochim Biophys Acta. 2012;1826:297–311.

    PubMed  CAS  Google Scholar 

  26. Yin M, Ren X, Zhang X, et al. Selective killing of lung cancer cells by miRNA-506 molecule through inhibiting NF-kappaB p65 to evoke reactive oxygen species generation and p53 activation. Oncogene. 2014. doi: 10.1038/onc.2013.597.

    Google Scholar 

  27. Wen SY, Lin Y, Yu YQ, et al. miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer. Oncogene. 2014. doi:10.1038/onc.2014.9.

    Google Scholar 

  28. Liu G, Sun Y, Ji P, et al. MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. J Pathol. 2014;233:308–18.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Guo F, Parker Kerrigan BC, Yang D, et al. Posttranscriptional regulatory network of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions. J Hematol Oncol. 2014;7:19.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Liu Z, Chen L, Zhang X, et al. RUNX3 regulates vimentin expression via miR-30a during epithelial–mesenchymal transition in gastric cancer cells. J Cell Mol Med. 2014;18:610–23.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T. NF-kappaB promotes epithelial–mesenchymal transition, migration, and invasion of pancreatic carcinoma cells. Cancer Lett. 2010;295:214–28.

    Article  PubMed  CAS  Google Scholar 

  32. Takeshita F, Patrawala L, Osaki M, et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther. 2010;18:181–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Lanford RE, Hildebrandt-Eriksen ES, Petri A, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 2010; 327:198–201.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgment

We thank K. Oda, M. Kasagi, S. Kohno, T. Kawano, and M. Aoyagi for their technical assistance. This work was supported in part by Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (Grant numbers 21591644, 21791295, 21791297, 215921014, and 21679006).

Author information

Authors and Affiliations

  1. Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan

    Shotaro Sakimura MD, Keishi Sugimachi MD, PhD, Junji Kurashige MD, PhD, Masami Ueda MD, Hidenari Hirata MD, Sho Nambara MD, Hisateru Komatsu MD, Tomoko Saito MD, Yuki Takano MD, Ryutaro Uchi MD, Etsuko Sakimura MD, Yoshiaki Shinden MD, Tomohiro Iguchi MD, PhD, Hidetoshi Eguchi MD, PhD & Koshi Mimori MD, PhD

  2. Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shotaro Sakimura MD, Yugo Oba MD & Sumio Hoka MD, PhD

Authors
  1. Shotaro Sakimura MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keishi Sugimachi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junji Kurashige MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masami Ueda MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hidenari Hirata MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sho Nambara MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hisateru Komatsu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tomoko Saito MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuki Takano MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ryutaro Uchi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Etsuko Sakimura MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoshiaki Shinden MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tomohiro Iguchi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hidetoshi Eguchi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yugo Oba MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Sumio Hoka MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Koshi Mimori MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Koshi Mimori MD, PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 102 kb)

Supplementary material 2 (PPTX 2101 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sakimura, S., Sugimachi, K., Kurashige, J. et al. The miR-506-Induced Epithelial–Mesenchymal Transition is Involved in Poor Prognosis for Patients with Gastric Cancer. Ann Surg Oncol 22 (Suppl 3), 1436–1443 (2015). https://doi.org/10.1245/s10434-015-4418-2

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-015-4418-2

Keywords

Search

Navigation