Skip to main content

Advertisement

SpringerLink
Log in

MiR-429 is linked to metastasis and poor prognosis in renal cell carcinoma by affecting epithelial-mesenchymal transition

  • Original Article
  • Published:
Tumor Biology

Abstract

MicroRNAs (miRNAs) have been proven to be important oncogenes and tumor suppressors in wide range of cancers, including renal cell carcinoma (RCC). In our study, we evaluated miRNA-429 as potential diagnostic/prognostic biomarker in 172 clear cell RCC patients and as a potential regulator of epithelial-mesenchymal transition (EMT) in vitro. We demonstrated that miR-429 is down-regulated in tumor tissue samples (P < 0.0001) and is significantly associated with cancer metastasis (P < 0.0001), shorter disease-free (P = 0.0105), and overall survival (P = 0.0020). In addition, ectopic expression of miR-429 in 786-0 RCC cells followed by TGF-β treatment led to increase in the levels of E-cadherin expression (P < 0.0001) and suppression of cellular migration (P < 0.0001) in comparison to TGF-β-treated controls. Taken together, our findings suggest that miR-429 may serve as promising diagnostic and prognostic biomarker in RCC patients. We further suggest that miR-429 has a capacity to inhibit loss of E-cadherin in RCC cells undergoing EMT and consequently attenuate their motility.

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

Similar content being viewed by others

References

  1. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374:135–45.

    Article  Google Scholar 

  2. Ma X, Gao Y, Fan Y, Ni D, Zhang Y, Chen W, et al. Overexpression of E2F1 promotes tumor malignancy and correlates with TNM stages in clear cell renal cell carcinoma. PLoS One. 2013;8:1–12.

    Article  Google Scholar 

  3. KY X, Wu S. Update on the treatment of metastatic clear cell and non-clear cell renal cell carcinoma. Biomark Res. 2015;3:1–5.

    Google Scholar 

  4. Ohtsuka M, Ling H, Doki Y, Mori M, Calin G. MicroRNA processing and human cancer. J Clin Med. 2015;4:1651–67.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Orom UA, Nielsen FC, Lund AH. MicroRNA-10a binds the 5’UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell. 2008;30:460–71.

    Article  PubMed  Google Scholar 

  6. Xu J, Yao Q, Hou Y, Xu M, Liu S, Yang L, et al. MiR-223/Ect2/p21 signaling regulates osteosarcoma cell cycle progression and proliferation. Biomed Pharmacother = Biomédecine Pharmacothérapie. 2013;67:381–6.

    Article  CAS  PubMed  Google Scholar 

  7. Huang N, Wu Z, Lin L, Zhou M, Wang L, Ma H, et al. MiR-338-3p inhibits epithelial-mesenchymal transition in gastric cancer cells by targeting ZEB2 and MACC1/Met/Akt signaling. Oncotarget. 2015;6:15222–34.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Liu YC, Zhang M, Qian J, Bao M, Meng X, Zhang S, et al. miR-134 functions as a tumor suppressor in cell proliferation and epithelial-to-mesenchymal transition by targeting KRAS in renal cell carcinoma cells. DNA Cell Biol. 2015;34:429–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 2008;283:14910–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang Y, Yang P, Wang XF. Microenvironmental regulation of cancer metastasis by miRNAs. Trends Cell Biol. 2014;24:153–60.

    Article  CAS  PubMed  Google Scholar 

  11. Sundararajan BS, Gengenbacher N, Stemmler MP, Kleemann JA, Brabletz T. The ZEB1/miR-200c feedback loop regulates invasion via actin interacting proteins MYLK and TKS5. Oncotarget. 2015;6:27083–96.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, Goodall GJ. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 2008;68:7846–54.

    Article  CAS  PubMed  Google Scholar 

  13. Ceppi P, Mudduluru P, Kumarswamy R, Rapa I, Scagliotti GV, Papotti M, Allgayer H. Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol Cancer Res. 2010;8:1207–16.

    Article  CAS  PubMed  Google Scholar 

  14. Xiong H, Hong J, Du W, Lin Y, Ren L, Wang Y, et al. Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J Biol Chem. 2012;287:5819–32.

    Article  CAS  PubMed  Google Scholar 

  15. Paul C. Renal cell carcinoma. Cancer Biomark. 2011;1–6:461–73.

    Google Scholar 

  16. Stewart-Merrill SB, Thompson RH, Boorjian SA, Psutka SP, Lohse CM, Cheville JC, et al. Oncologic surveillance after surgical resection for renal cell carcinoma: a novel risk-based approach. J Clin Oncol. 2015;33:4151–7.

    Article  PubMed  Google Scholar 

  17. Chan SH, Wang LH. Regulation of cancer metastasis by microRNAs. J Biomed Sci. 2015;22:9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yoshino H, Enokida H, Itesako T, Tatarano S, Kinoshita T, Fuse M, et al. Epithelial-mesenchymal transition-related microRNA-200s regulate molecular targets and pathways in renal cell carcinoma. J Hum Genet. 2013;4:1–9.

    Google Scholar 

  19. Sun Y, Shen S, Liu X, Tang H, Wang Z, Yu Z, et al. MiR-429 inhibits cells growth and invasion and regulates EMT-related marker genes by targeting Onecut2 in colorectal carcinoma. Mol Cell Biochem. 2014;390:19–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tang J, Li L, Huang W, Sui C, Yang Y, Lin X, et al. MiR-429 increases the metastatic capability of HCC via regulating classic Wnt pathway rather than epithelial-mesenchymal transition. Cancer Lett. 2015;364:33–43.

    Article  CAS  PubMed  Google Scholar 

  21. Wang Y, Dong X, Hu B, Wang XJ, Wang Q, Wang WL, et al. The effects of Micro-429 on inhibition of cervical cancer cells through targeting ZEB1 and CRKL. Biomed Pharmacother. 2016;80:311–21.

    Article  CAS  PubMed  Google Scholar 

  22. Wang F, Jiang C, Sun Q, Yan F, Wang L, Fu Z, et al. Downregulation of miR-429 and inhibition of cell migration and invasion in nasopharyngeal carcinoma. Mol Med Rep. 2016;13:3236–42.

    CAS  PubMed  Google Scholar 

  23. Zhu Q, He J, Chen D, Zhang B, Xu L, Ma H, et al. Expression of miR-29c, miR-93, and miR-429 as potential biomarkers for detection of early stage non-small lung cancer. PLoS One. 2014;9:2.

    Article  Google Scholar 

  24. Halvorsen AR, Bjaanæs M, LeBlanc M, Holm AM, Bolstad N, Rubio L, et al. A unique set of 6 circulating microRNAs for early detection of non-small cell lung cancer. Oncotarget. 2016.

  25. Wu CL, Ho JY, Chou SC, Yu DS. MiR-429 reverses epithelial-mesenchymal transition by restoring E-cadherin expression in bladder cancer. Oncotarget. 2014.

  26. Chen Y, Xiao Y, Ge W, Zhou K, Wen J, Yan W, et al. miR-200b inhibits TGF-β1-induced epithelial-mesenchymal transition and promotes growth of intestinal epithelial cells. Cell Death Dis. 2013;4:e541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu CL, Ho JY, Chou SC, Yu DS. MiR-429 reverses epithelial-mesenchymal transition by restoring E-cadherin expression in bladder cancer. Oncotarget. 2016.

  28. Jingushi K, Ueda Y, Kitae K, Hase H, Egawa H, Ohshio I, et al. miR-629 targets TRIM33 to promote TGFβ/Smad signaling and metastatic phenotypes in ccRCC. Mo Cancer Res. 2014;13:565–74.

  29. Huang W, Cen S, Kang X, Wang W, Wang Y, Chen X. TGF-β1-induced Fascin1 promotes cell invasion and metastasis of human 786-0 renal carcinoma cells. Acta Histochem. 2016;118:144–51.

    Article  CAS  PubMed  Google Scholar 

  30. Fu H, Hu Z, Wen J, Wang K, Liu Y. TGF-β promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. Acta Biochim Biophys Sin Shanghai. 2009;41:648–56.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This study was supported by grant no. 15-34678A of the Czech Ministry of Health, by the Ministry of Education, Youth and Sports of the Czech Republic under the project CEITEC 2020 (LQ1601), the Project RVO (MOU, 00209805), and The Ministry of Education, Youth and Sports for the Project BBMRI CZ (LM2010004).

Author information

Authors and Affiliations

  1. Central European Institute of Technology (CEITEC), Masaryk University, University Campus Bohunice, Building A35, Room 217, Kamenice 5, 625 00, Brno, Czech Republic

    Tana Machackova, Hana Mlcochova, Marek Svoboda & Ondrej Slaby

  2. Department of Urologic Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic

    Michal Stanik & Jan Dolezel

  3. Department of Urology, University Hospital Brno and Masaryk University, Brno, Czech Republic

    Michal Fedorko & Dalibor Pacik

  4. Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic

    Alexandr Poprach, Marek Svoboda & Ondrej Slaby

Authors
  1. Tana Machackova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hana Mlcochova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michal Stanik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Dolezel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michal Fedorko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dalibor Pacik
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexandr Poprach
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marek Svoboda
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ondrej Slaby
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ondrej Slaby.

Ethics declarations

All patients included in the study signed informed consent forms and the study was approved by the local Ethical Board at the Masaryk Memorial Cancer Institute and University Hospital Brno.

Conflicts of interest

None.

Additional information

Tana Machackova and Hana Mlcochova contributed equally to the manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Machackova, T., Mlcochova, H., Stanik, M. et al. MiR-429 is linked to metastasis and poor prognosis in renal cell carcinoma by affecting epithelial-mesenchymal transition. Tumor Biol. 37, 14653–14658 (2016). https://doi.org/10.1007/s13277-016-5310-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5310-9

Keywords

Search

Navigation