Skip to main content

Advertisement

SpringerLink
Log in

miR-597-5p inhibits cell growth and promotes cell apoptosis by targeting ELK1 in pancreatic cancer

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Pancreatic cancer is a malignant disease with poor prognosis. Emerging evidences have showed that miR-597-5p is closely related to tumor development. However, the functional roles of miR-597-5p in pancreatic cancer remain unknown. This study aimed to investigate the expression of miR-597-5p in pancreatic cancer tissues and cells, and explored its regulatory mechanism during pancreatic cancer progression. Pancreatic cancer and adjacent tissues were obtained to detect the expression of miR-597-5p by RT-qPCR. Cell growth, apoptosis, and related protein expression were, respectively, tested by CCK-8 assay, cell formation, wound healing, Transwell assay, flow cytometry, and western blotting. Finally, the pancreatic cancer mice model was constructed. In vitro and in vivo results showed that miR-597-5p expression was down-regulated in pancreatic cancer tissues and cell lines, and increased the overall survival of pancreatic cancer patients. Moreover, miR-597-5p decreased pancreatic cancer cell viability, reduced relative wound width, suppressed colony formation and decreased invasive cell number, as well as reduced the expression of proliferating cell nuclear antigen (PCNA), Ki67, Cyclin D1, N-cad, and Bcl-2. Meanwhile, it increased pancreatic cancer cell apoptosis and the expression of E-cad, cleaved caspase 3, and Bax. The dual-luciferase reporter assay confirmed miR-597-5p could directly target e-twenty six like-1 (ELK1) oncogene. The reduction of cell growth and the induction of cell apoptosis induced by miR-597-5p were reversed by ELK1. In addition, miR-597-5p inhibited the growth of pancreatic cancer in vivo. This study demonstrated that miR-597-5p may be a novel suppressor of pancreatic cancer. It inhibits pancreatic cancer cell growth and promotes apoptosis by the down-regulation of ELK1 in vitro and in vivo.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Chua YJ, Cunningham D. Adjuvant treatment for resectable pancreatic cancer. J Clin Oncol. 2005;23(20):4532–7. https://doi.org/10.1200/jco.2005.17.954.

    Article  CAS  PubMed  Google Scholar 

  2. Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Coffee and alcohol consumption and the risk of pancreatic cancer in two prospective United States cohorts. Cancer Epidemiol Biomark Prev. 2001;10(5):429–37.

    CAS  Google Scholar 

  3. Li B-Q, Wang L, Li J, Zhou L, Zhang T-P, Guo J-C, et al. Surgeons’ knowledge regarding the diagnosis and management of pancreatic cancer in China: a cross-sectional study. BMC Health Serv Res. 2017;17(1):395. https://doi.org/10.1186/s12913-017-2345-6.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114–7. https://doi.org/10.1038/nature09515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China 2015. CA Cancer J Clin. 2016;66(2):115–32. https://doi.org/10.3322/caac.21338.

    Article  PubMed  Google Scholar 

  6. Beger HG, Rau B, Gansauge F, Leder G, Schwarz M, Poch B. Pancreatic cancer–low survival rates. Dtsch Arzteblatt Int. 2008;105(14):255–62. https://doi.org/10.3238/arztebl.2008.0255.

    Article  Google Scholar 

  7. van Vuurden DG, Hulleman E, Irandoust M, Biesmann D, van den Berg T, Aronica E, et al. SIRPαα is transcriptionally downregulated by epigenetic silencing in medulloblastoma. J Mol Clin Med. 2018;1(3):157–68.

    Google Scholar 

  8. Li MF, Li J, Ding XF, Cheng SY. MicroRNA and cancer. Aaps J. 2010;12:309–317. https://doi.org/10.1208/s12248-010-9194-0

  9. He J, Mai J, Li Y, Chen L, Xu H, Zhu X, et al. miR-597 inhibits breast cancer cell proliferation, migration and invasion through FOSL2. Oncol Rep. 2017;37(5):2672–8. https://doi.org/10.3892/or.2017.5558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Frampton AE, Castellano L, Colombo T, Giovannetti E, Krell J, Jacob J, et al. MicroRNAs cooperatively inhibit a network of tumor suppressor genes to promote pancreatic tumor growth and progression. Gastroenterology. 2014;146(1):268–77.e18. https://doi.org/10.1053/j.gastro.2013.10.010.

    Article  CAS  PubMed  Google Scholar 

  11. Felix TF, Lopez Lapa RM, de Carvalho M, Bertoni N, Tokar T, Oliveira RA, et al. MicroRNA modulated networks of adaptive and innate immune response in pancreatic ductal adenocarcinoma. PLoS ONE. 2019;14(5):e0217421. https://doi.org/10.1371/journal.pone.0217421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hollenhorst PC, McIntosh LP, Graves BJ. Genomic and biochemical insights into the specificity of ETS transcription factors. Annu Rev Biochem. 2011;80:437–71. https://doi.org/10.1146/annurev.biochem.79.081507.103945.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ahmad A, Zhang W, Wu M, Tan S, Zhu TJG. Tumor-suppressive miRNA-135a inhibits breast cancer cell proliferation by targeting ELK1 and ELK3 oncogenes. Genes Genom. 2018;40(3):243–51. https://doi.org/10.1007/s13258-017-0624-6.

    Article  CAS  Google Scholar 

  14. National Research Council Institute for Laboratory Animal R. Guide for the Care and Use of Laboratory Animals. Washington: National Academies Press; 1996.

    Google Scholar 

  15. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, CA). 2001;25(4):402–8. https://doi.org/10.1006/meth.2001.1262.

    Article  CAS  Google Scholar 

  16. Wang Y, Kuramitsu Y, Yoshino S, Takashima M, Zhang X, Ueno T, et al. Screening for serological biomarkers of pancreatic cancer by two-dimensional electrophoresis and liquid chromatography-tandem mass spectrometry. Oncol Rep. 2011;26(1):287–92. https://doi.org/10.3892/or.2011.1278.

    Article  CAS  PubMed  Google Scholar 

  17. Yu S, Lu Z, Liu C, Meng Y, Ma Y, Zhao W, et al. miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Can Res. 2010;70(14):6015–25. https://doi.org/10.1158/0008-5472.can-09-4531.

    Article  CAS  Google Scholar 

  18. Zoller M. Pancreatic cancer diagnosis by free and exosomal miRNA. World J Gastrointest Pathophysiol. 2013;4(4):74–90. https://doi.org/10.4291/wjgp.v4.i4.74.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zhao G, Wang B, Liu Y, Zhang JG, Deng SC, Qin Q, et al. miRNA-141, downregulated in pancreatic cancer, inhibits cell proliferation and invasion by directly targeting MAP4K4. Mol Cancer Ther. 2013;12(11):2569–80. https://doi.org/10.1158/1535-7163.mct-13-0296.

    Article  CAS  PubMed  Google Scholar 

  20. Zhang XY, Liu DJ, Yuan RB, Zhang DH, Li SR, Zhang SH, et al. Low expression of miR-597 is correlated with tumor stage and poor outcome in breast cancer. Eur Rev Med Pharmacol Sci. 2018;22(2):456–60. https://doi.org/10.26355/eurrev_201801_14195.

    Article  PubMed  Google Scholar 

  21. Xie L, Jiang T, Cheng A, Zhang T, Huang P, Li P, et al. MiR-597 targeting 14–3-3sigma enhances cellular invasion and EMT in nasopharyngeal carcinoma cells. Curr Mol Pharmacol. 2019;12(2):105–14. https://doi.org/10.2174/1874467212666181218113930.

    Article  CAS  PubMed  Google Scholar 

  22. Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22(7):894–907. https://doi.org/10.1101/gad.1640608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Janknecht R, Nordheim A. Elk-1 protein domains required for direct and SRF-assisted DNA-binding. Nucleic Acids Res. 1992;20(13):3317–24. https://doi.org/10.1093/nar/20.13.3317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hipskind RA, Rao VN, Mueller CG, Reddy ES, Nordheim A. Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Nature. 1991;354(6354):531–4. https://doi.org/10.1038/354531a0.

    Article  CAS  PubMed  Google Scholar 

  25. Marais R, Wynne J, Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993;73(2):381–93. https://doi.org/10.1016/0092-8674(93)90237-k.

    Article  CAS  PubMed  Google Scholar 

  26. Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S. The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci. 2000;20(12):4563–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hodge C, Liao J, Stofega M, Guan K, Carter-Su C, Schwartz J. Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2. J Biol Chem. 1998;273(47):31327–36. https://doi.org/10.1074/jbc.273.47.31327.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Not applicable.

Author information

Author notes

  1. Shizong Li and Xianglu Li have contributed equally to the work.

Authors and Affiliations

  1. Department of Hepatobiliary and Pancreatic Surgery, Hainan General Hospital, Haikou City, 570311, Hainan Province, China

    Shizong Li

  2. Department of Ward 1 of Oncology, Hainan General Hospital, No. 19, Xiuhua Road, Haikou City, 570311, Hainan Province, China

    Xianglu Li, Xuehua Xing & Lin Wang

Authors
  1. Shizong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xianglu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xuehua Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SZL and XLL conceived and designed the experiments, XHX analyzed and interpreted the results of the experiments, and LW performed the experiments.

Corresponding author

Correspondence to Xianglu Li.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests, and all authors should confirm its accuracy.

Ethics approval and consent to participate

All animal experiments were followed by the Guide for the Care and Use of Laboratory Animals and approved by the Ethical Committee of Hainan General Hospital. The specimens of pancreatic cancer and adjacent tissues were collected from the patients who were diagnosed with pancreatic cancer in Hepatobiliary Surgery of Hainan General Hospital. The informed consents for each patient were obtained and the procedures were approved by the Ethics Committee of Hainan General Hospital (Approval no.[2019]49).

Informed consent

Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S., Li, X., Xing, X. et al. miR-597-5p inhibits cell growth and promotes cell apoptosis by targeting ELK1 in pancreatic cancer. Human Cell 33, 1165–1175 (2020). https://doi.org/10.1007/s13577-020-00395-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-020-00395-x

Keywords

Search

Navigation