SpringerLink
Log in

siRNA-mediated downregulation of BATF3 diminished proliferation and induced apoptosis through downregulating c-Myc expression in chronic myelogenous leukemia cells

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Objective

Despite considerable improvement in therapeutic approaches to chronic myeloid leukemia (CML) treatment, this malignancy is considered incurable due to resistance. However, investigating the molecular mechanism of CML may give rise to the development of extremely efficient targeted therapies that improve the prognosis of patients. Basic leucine zipper transcription factor ATF-like3 (BATF3), as transcription factor, is considered a key regulator of cellular activities and its function has been evaluated in tumor development and growth in several cancer types. This study aimed to evaluate the potential of the cellular impact of siRNA-mediated downregulation of BATF3 on CML cancer cells through cell proliferation, induction of apoptosis, and cell cycle distribution.

Materials and methods

The transfection of BATF3 siRNA to K562 CML cells was performed by electroporation device. To measure cellular viability and apoptosis, MTT assay and Annexin V/PI staining were carried out, respectively. Also, cell cycle assay and flow cytometry instrument were applied to assess cell cycle distribution of K562 cells. For more validation, mRNA expression of correlated genes was relatively evaluated by quantitative real-time polymerase chain reaction (qRT-PCR).

Results

The data indicated that siRNA-mediated BATF3 inactivating severely promoted the cell apoptosis. Also, the targeted therapy led to high expression of Caspase-3 gene and Bax/Bcl-2 ratio. Silenced BATF3 also induced cell cycle arrest in phase sub-G1 compared to control. Finally, a noticeable decrement was obtained in c-Myc gene expression through suppression of BATF3 in CML cells.

Conclusion

The findings of this research illustrated the suppression of BATF3 as an effective targeted therapy strategy for CML.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Data availability

All data generated or analyzed during this study are avaidable upon request.

References

  1. Chereda B, Melo JV (2015) Natural course and biology of CML. Ann Hematol 94(2):107–121

    Article  CAS  Google Scholar 

  2. Cortes JE, Talpaz M, Kantarjian H (1996) Chronic myelogenous leukemia: a review. Am J Med 100(5):555–570

    Article  CAS  PubMed  Google Scholar 

  3. Jabbour E, Kantarjian H (2018) Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol 93(3):442–459

    Article  PubMed  Google Scholar 

  4. Aladağ E, Haznedaroğlu İC (2019) Current perspectives for the treatment of chronic myeloid leukemia. Turk J Med Sci 49(1):1–10

    PubMed  PubMed Central  Google Scholar 

  5. Chavez-Gonzalez A, Bakhshinejad B, Pakravan K, Guzman ML, Babashah S (2017) Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer. Cell Oncol 40(1):1–20

    Article  CAS  Google Scholar 

  6. Jabbour E, Kantarjian H (2020) Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. Am J Hematol 95(6):691–709

    Article  CAS  PubMed  Google Scholar 

  7. Jabbour E, Parikh SA, Kantarjian H, Cortes J (2011) Chronic myeloid leukemia: mechanisms of resistance and treatment. Hematol Oncol Clin North Am 25(5):981

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hashimoto I, Oshima T (2022) Claudins and gastric cancer: an overview. Cancers 14(2):290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wagner EF, Eferl R (2005) Fos/AP-1 proteins in bone and the immune system. Immunol Rev 208(1):126–140

    Article  CAS  PubMed  Google Scholar 

  10. Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3(11):859–868

    Article  CAS  PubMed  Google Scholar 

  11. Echlin DR, Tae H-J, Mitin N, Taparowsky EJ (2000) B-ATF functions as a negative regulator of AP-1 mediated transcription and blocks cellular transformation by Ras and Fos. Oncogene 19(14):1752–1763

    Article  CAS  PubMed  Google Scholar 

  12. Murphy TL, Tussiwand R, Murphy KM (2013) Specificity through cooperation: BATF–IRF interactions control immune-regulatory networks. Nat Rev Immunol 13(7):499–509

    Article  CAS  PubMed  Google Scholar 

  13. Benckendorff J, Kuchar J, Leithäuser F, Zahn M, Möller P (2021) Usefulness of BATF3 immunohistochemistry in diagnosing classical Hodgkin Lymphoma. Diagnostics 11(6):1123

    Article  CAS  PubMed  Google Scholar 

  14. Mojtahedi H, Yazdanpanah N, Rezaei N (2021) Chronic myeloid leukemia stem cells: targeting therapeutic implications. Stem Cell Res Ther 12(1):603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Singh VK, Coumar MS (2019) Chronic myeloid leukemia: existing therapeutic options and strategies to Overcome Drug Resistance. Mini Rev Med Chem 19(4):333–345

    Article  CAS  PubMed  Google Scholar 

  16. Meenakshi Sundaram DN, Jiang X, Brandwein JM, Valencia-Serna J, Remant KC, Uludağ H (2019) Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options. Drug Discovery Today 24(7):1355–1369

    Article  CAS  PubMed  Google Scholar 

  17. Dessie G, Derbew Molla M, Shibabaw T, Ayelign B (2020) Role of stem-cell transplantation in leukemia treatment. Stem Cell Cloning 13:67–77

    Google Scholar 

  18. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M et al (2008) Batf3 deficiency reveals a critical role for CD8alpha + dendritic cells in cytotoxic T cell immunity. Science 322(5904):1097–1100

    Article  CAS  PubMed  Google Scholar 

  19. Tussiwand R, Lee WL, Murphy TL, Mashayekhi M, Kc W, Albring JC et al (2012) Compensatory dendritic cell development mediated by BATF-IRF interactions. Nature 490(7421):502–507

    Article  CAS  PubMed  Google Scholar 

  20. Cao L, Liu Y, Wang D, Huang L, Li F, Liu J et al (2018) MiR-760 suppresses human Colorectal cancer growth by targeting BATF3/AP-1/cyclinD1 signaling. J Exp Clin Cancer Res 37(1):83

    Article  PubMed  PubMed Central  Google Scholar 

  21. Li P, Weng Z, Li P, Hu F, Zhang Y, Guo Z et al (2021) BATF3 promotes malignant phenotype of colorectal cancer through the S1PR1/p-STAT3/miR-155-3p/WDR82 axis. Cancer Gene Ther 28(5):400–412

    Article  CAS  PubMed  Google Scholar 

  22. Vrzalikova K, Ibrahim M, Vockerodt M, Perry T, Margielewska S, Lupino L et al (2018) S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells. Leukemia 32(1):214–223

    Article  CAS  PubMed  Google Scholar 

  23. Gonzalez MS, De Brasi CD, Bianchini M, Gargallo P, Moiraghi B, Bengió R et al (2010) BAX/BCL-XL gene expression ratio inversely correlates with Disease progression in chronic Myeloid Leukemia. Blood Cells Mol Dis 45(3):192–196

    Article  CAS  PubMed  Google Scholar 

  24. Carter BZ, Mak PY, Mu H, Zhou H, Mak DH, Schober W et al (2016) Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med 8(355):355ra117-355ra117

    Article  PubMed  PubMed Central  Google Scholar 

  25. Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E, Boise LH (2013) Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol 14:32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Parrish AB, Freel CD, Kornbluth S (2013) Cellular mechanisms controlling caspase activation and function. Cold Spring Harb Perspect Biol 5(6):a008672

    Article  PubMed  PubMed Central  Google Scholar 

  27. Di Bacco AM, Cotter TG (2002) p53 expression in K562 cells is associated with caspase-mediated cleavage of c-ABL and BCR-ABL protein kinases. Br J Haematol 117(3):588–597

    Article  PubMed  Google Scholar 

  28. Lu Y, Chen G-Q (2011) Effector caspases and Leukemia. Int J Cell Biol 2011:738301

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sodaro G, Cesaro E, Montano G, Blasio G, Fiorentino F, Romano S et al (2018) Role of ZNF224 in c-Myc repression and imatinib responsiveness in chronic Myeloid Leukemia. Oncotarget 9(3):3417

    Article  PubMed  Google Scholar 

  30. Sharma N, Magistroni V, Piazza R, Citterio S, Mezzatesta C, Khandelwal P et al (2015) BCR/ABL1 and BCR are under the transcriptional control of the MYC oncogene. Mol Cancer 14(1):1–11

    Article  CAS  Google Scholar 

  31. Zhu J, Sunohara M, Benyoucef A, Brand M (2018) Targeting the process of C-MYC stabilization in chronic myelogenous Leukemia. Exp Hematol 64:S114

    Article  Google Scholar 

  32. Lollies A, Hartmann S, Schneider M, Bracht T, Weiß AL, Arnolds J et al (2018) An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin Lymphoma and anaplastic large cell Lymphoma. Leukemia 32(1):92–101

    Article  CAS  PubMed  Google Scholar 

  33. Gavrilov K, Saltzman WM (2012) Therapeutic siRNA: principles, challenges, and strategies. Yale J Biol Med 85(2):187

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Petri S, Meister G (2013) siRNA design principles and off-target effects. Target Identif Valid Drug Discov. https://doi.org/10.1007/978-1-62703-311-4_4

    Article  Google Scholar 

  35. Meng Z, Lu M (2017) RNA interference-induced innate immunity, off-target effect, or immune adjuvant? Front Immunol 8:331

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are thankful for supports from the Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Funding

We didn’t receive grant for this research.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran

    Reza Dabbaghipour, SMB Tabei & Mona Entezam

  2. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Dabbaghipour, Vahid Khaze Shahgoli, Sahar Safaei, Mohammad Amini, Dariush Shanehbandi, Omid Rahbar Farzam & Behzad Baradaran

  3. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Behzad Baradaran

  4. Cancer and Inflammation Research, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Vahid Khaze Shahgoli

  5. Pharmaceutical Analysis Research Center, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Dariush Shanehbandi

  6. Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, IR, Iran

    Mona Entezam

Authors
  1. Reza Dabbaghipour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vahid Khaze Shahgoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sahar Safaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Amini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. SMB Tabei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dariush Shanehbandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Omid Rahbar Farzam
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Behzad Baradaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mona Entezam
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RD: Conceptualization, investigation, formal analysis, Writing—Original Draft. VKS: Validation, formal analysis, data curation. SS: Validation, formal analysis, data curation. MA: Validation, formal analysis, data curation. SMBT: Writing—review & editing, data curation. DS: Writing—review & editing, data curation. ORF: Validation. EM: Supervision, project administration. BB : Supervision, project administration.

Corresponding authors

Correspondence to Behzad Baradaran or Mona Entezam.

Ethics declarations

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical statement

All experiments and procedures were conducted in compliance with the ethical principles of Shiraz University of Medical Science, Shiraz, Iran and approved by the regional ethical committee for medical research.

Additional information

Publisher’s Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dabbaghipour, R., Khaze Shahgoli, V., Safaei, S. et al. siRNA-mediated downregulation of BATF3 diminished proliferation and induced apoptosis through downregulating c-Myc expression in chronic myelogenous leukemia cells. Mol Biol Rep 51, 100 (2024). https://doi.org/10.1007/s11033-023-09059-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11033-023-09059-z

Keywords

Search

Navigation