Skip to main content
SpringerLink
Log in

MicroRNA-409-5p Inhibits GIST Tumorigenesis and Improves Imatinib Resistance by Targeting KDM4D Expression

  • Original Article
  • Published:
Current Medical Science Aims and scope Submit manuscript

Abstract

Objective

Gastrointestinal stromal tumors (GISTs) can rapidly proliferate through angiogenesis. Previous studies indicated the potential influence of microRNA on the progression of tumor immature angiogenesis. This study aimed to explore the specific mechanism by which microRNA-409-5p (miR-409-5p) contributes to GIST.

Methods

To identify genes potentially involved in the development and progression of GIST, the differences of miR-409-5p between tumors and adjacent tissues were first analyzed. Following this analysis, target genes were predicted. To further investigate the function of miRNA in GIST cells, two GIST cell lines (GIST-T1 and GIST882) were transfected with lentiviruses that stably expressed miR-409-5p and scrambled miRNA (negative control). Later, the cells were subjected to Western blotting and ELSA to determine any differences in angiogenesis-related genes.

Results

In GISTs, there was a decrease in the expression levels of miR-409-5p compared to the adjacent tissues. It was observed that the upregulation of miR-409-5p in GIST cell lines effectively inhibited the proteins hypoxia-inducible transcription factor 1β (HIF1β) and vascular endothelial growth factor A (VEGF-A). Further investigations revealed that miR-409-5p acted as an inhibitor of angiogenesis by binding to the 3′-UTR of Lysine-specific demethylase 4D (KDM4D) mRNA. Moreover, the combination of miR-409-5p with imatinib enhanced its inhibitory effect on angiogenesis.

Conclusion

This study demonstrated that the miRNA-409-5p/KDM4D/HIF1β/VEGF-A signaling pathway could serve as a novel target for the development of therapeutic strategies for the treatment of imatinib-resistance in GIST patients.

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

Similar content being viewed by others

References

  1. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer, 2011,11(12):865–878

    Article  CAS  PubMed  Google Scholar 

  2. Miettinen M, Lasota J. Histopathology of gastrointestinal stromal tumor. J Surg Oncol, 2011,104(8):865–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Joensuu H, Hohenberger P, Corless CL. Gastrointestinal stromal tumour. Lancet, 2013,382(9896):973–983

    Article  CAS  PubMed  Google Scholar 

  4. ESMO/European Sarcoma Network Working Group. Gastrointestinal stromal tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2012,23(Suppl 7):vii49–55

    Google Scholar 

  5. Goettsch WG, Bos SD, Breekveldt-Postma N, et al. Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer, 2005,41(18):2868–2872

    Article  PubMed  Google Scholar 

  6. Roberts PJ, Eisenberg B. Clinical presentation of gastrointestinal stromal tumors and treatment of operable disease. Eur J Cancer, 2002,38 Suppl 5:S37–S38

    Article  PubMed  Google Scholar 

  7. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med, 2002,347(7):472–480

    Article  CAS  PubMed  Google Scholar 

  8. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard-versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol, 2008,26(4):620–625

    Article  CAS  PubMed  Google Scholar 

  9. Nishida T, Shirao K, Sawaki A, et al. Efficacy and safety profile of imatinib mesylate (ST1571) in Japanese patients with advanced gastrointestinal stromal tumors: a phase II study (STI571B1202). Int J Clin Oncol, 2008,13(3):244–251

    Article  CAS  PubMed  Google Scholar 

  10. Joensuu H, Vehtari A, Riihimäki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. The Lancet Oncology, 2012,13(3):265–274

    Article  PubMed  Google Scholar 

  11. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell, 2009,136(2):215–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mattick JS. The genetic signatures of noncoding RNAs. PLoS Genet, 2009,5(4):e1000459

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature, 2005,435(7043):834–838

    Article  CAS  PubMed  Google Scholar 

  14. Ji J, Shi J, Budhu A, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med, 2009,361(15):1437–1447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov, 2013,12(11):847–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bader AG. miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet, 2012,3:120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bader AG, Brown D, Stoudemire J, Lammers P. Developing therapeutic microRNAs for cancer. Gene Ther, 2011,18(12):1121–1126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen L, Zheng J, Zhang Y, et al. Tumor-specific expression of microRNA-26a suppresses human hepatocellular carcinoma growth via cyclin-dependent and -independent pathways. Mol Ther, 2011,19(8):1521–1528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hartmann P, Zhou Z, Natarelli L, et al. Endothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4. Nat Commun, 2016,7:10521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jeon YJ, Kim T, Park D, et al. miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC. Nat Commun, 2018,9(1):5110

    Article  PubMed  PubMed Central  Google Scholar 

  21. Josson S, Gururajan M, Hu P, et al. miR-409-3p/-5p promotes tumorigenesis, epithelial-to-mesenchymal transition, and bone metastasis of human prostate cancer. Clin Cancer Res, 2014,20(17):4636–4646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Prakash R, John AA, Singh D. miR-409-5p negatively regulates Wnt/Beta catenin signaling pathway by targeting Lrp-8. J Cell Physiol, 2019,234(12):23507–23517

    Article  CAS  PubMed  Google Scholar 

  23. Yu H, Xing H, Han W, et al. MicroRNA-409-5p is upregulated in breast cancer and its downregulation inhibits cancer development through downstream target of RSU1. Tumour Biol, 2017,39(5):1010428317701647

    Article  PubMed  Google Scholar 

  24. de Rinaldis E, Gazinska P, Mera A, et al. Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control. BMC Genomics, 2013,14:643

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wang G, Yang X, Li C, et al. PIK3R3 induces epithelial-to-mesenchymal transition and promotes metastasis in colorectal cancer. Mol Cancer Ther, 2014,13(7):1837–1847

    Article  CAS  PubMed  Google Scholar 

  26. Lu X, Kang Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res, 2010,16(24):5928–5935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Eswarappa SM, Fox PL. Antiangiogenic VEGF-Ax: A New Participant in Tumor Angiogenesis. Cancer Res, 2015,75(14):2765–2769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer, 2013,13(12):871–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene, 2010,29(5):625–634

    Article  CAS  PubMed  Google Scholar 

  30. Kumar MS, Lu J, Mercer KL, et al. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet, 2007,39(5):673–677

    Article  CAS  PubMed  Google Scholar 

  31. Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov, 2010,9(10):775–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer, 2015,15(6):321–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bai R, Weng C, Dong H, et al. MicroRNA-409-3p suppresses colorectal cancer invasion and metastasis partly by targeting GAB1 expression. Int J Cancer, 2015,137(10):2310–2322

    Article  CAS  PubMed  Google Scholar 

  34. Hu F, Li H, Liu L, et al. Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1beta/VEGFA signalling. Mol Cancer, 2018,17(1):107

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol, 2019,20(1):21–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Issler O, Chen A. Determining the role of microRNAs in psychiatric disorders. Nat Rev Neurosci, 2015,16(4):201–212

    Article  CAS  PubMed  Google Scholar 

  37. Kota J, Chivukula RR, O’Donnell KA, et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell, 2009,137(6):1005–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med, 2013,368(18):1685–1694

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgmenets

We are grateful to the members of Gui-hua WANG’s lab and Jun-bo HU’s lab for their critical input and suggestions.

Author information

Authors and Affiliations

  1. GI Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Cheng Qiu, Yong-dong Feng & Xi Yang

Authors
  1. Cheng Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong-dong Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xi Yang.

Ethics declarations

All authors have no conflicts of interest to declare.

Additional information

The study was supported by the National Natural Science Foundation of China (No. 81372323 and No. 81802426).

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qiu, C., Feng, Yd. & Yang, X. MicroRNA-409-5p Inhibits GIST Tumorigenesis and Improves Imatinib Resistance by Targeting KDM4D Expression. CURR MED SCI 43, 935–946 (2023). https://doi.org/10.1007/s11596-023-2715-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-023-2715-8

Key words

Search

Navigation