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Transcription factor c-Myb: novel prognostic factor in osteosarcoma

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Abstract

The transcription factor c-Myb is an oncoprotein promoting cell proliferation and survival when aberrantly activated/expressed, thus contributing to malignant transformation. Overexpression of c-Myb has been found in leukemias, breast, colon and adenoid cystic carcinoma. Recent studies revealed its expression also in osteosarcoma cell lines and suggested its functional importance during bone development. However, the relevance of c-Myb in control of osteosarcoma progression remains unknown. A retrospective clinical study was carried out to assess a relationship between c-Myb expression in archival osteosarcoma tissues and prognosis in a cohort of high-grade osteosarcoma patients. In addition, MYB was depleted in metastatic osteosarcoma cell lines SAOS-2 LM5 and 143B and their growth, chemosensitivity, migration and metastatic activity were determined. Immunohistochemical analysis revealed that high c-Myb expression was significantly associated with poor overall survival in the cohort and metastatic progression in young patients. Increased level of c-Myb was detected in metastatic osteosarcoma cell lines and its depletion suppressed their growth, colony-forming capacity, migration and chemoresistance in vitro in a cell line-dependent manner. MYB knock-out resulted in reduced metastatic activity of both SAOS-2 LM5 and 143B cell lines in immunodeficient mice. Transcriptomic analysis revealed the c-Myb-driven functional programs enriched for genes involved in the regulation of cell growth, stress response, cell adhesion and cell differentiation/morphogenesis. Wnt signaling pathway was identified as c-Myb target in osteosarcoma cells. Taken together, we identified c-Myb as a negative prognostic factor in osteosarcoma and showed its involvement in the regulation of osteosarcoma cell growth, chemosensitivity, migration and metastatic activity.

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The raw data obtained and analyzed from this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank Merel van Gogh and Sabina Sevcikova for proofreading the manuscript.

Funding

This work was supported by the by Ministry of Health of the Czech Republic grant NV18-07-00073, Czech Science Foundation project 20-22984S and by the European Regional Development Fund—Project ENOCH (No. CZ.02.1.01/0.0/16_019/0000868).

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Authors and Affiliations

  1. Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic

    Kamila Říhová, Monika Dúcka, Ladislava Vymětalová, Martin Šrámek, Filip Trčka, Stanislav Drápela, Barbora Pavlatovská, Lucia Knopfová, Jan Šmarda, Karel Souček & Petr Beneš

  2. International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic

    Monika Dúcka, Iva Staniczková Zambo, Ladislava Vymětalová, Martin Šrámek, Filip Trčka, Stanislav Drápela, Radek Fedr, Tereza Suchánková, Danica Zapletalová, Peter Múdry, Lucia Knopfová, Karel Souček & Petr Beneš

  3. 1st Department of Pathological Anatomy, School of Medicine, Masaryk University, Brno and St. Anne’s University Hospital, Brno, Czech Republic

    Iva Staniczková Zambo

  4. CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic

    Jan Verner

  5. Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, v.v.i., Brno, Czech Republic

    Stanislav Drápela, Radek Fedr, Tereza Suchánková & Karel Souček

  6. Department of Internal Medicine – Hematology and Oncology, University Hospital Brno & Masaryk University, Brno, Czech Republic

    Eva Ondroušková

  7. Department of Pathology, University Hospital Brno, Brno, Czech Republic

    Irena Kubelková

  8. Department of Pediatric Oncology, University Hospital Brno and School of Medicine, Masaryk University, Brno, Czech Republic

    Danica Zapletalová & Peter Múdry

  9. Masaryk Memorial Cancer Institute, Brno, Czech Republic

    Štěpán Tuček & Dagmar Adámková Krákorová

  10. Institute of Physiology, University of Zurich, Zurich, Switzerland

    Lubor Borsig

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  1. Kamila Říhová
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Contributions

KR, MD, LV, MS, FT, EO, TS, BP carried out in vitro experiments; RF performed cell sorting; JV and SD performed in vivo experiments; DZ, ST, PM, DAK collected patient cohort and clinical data; ISZ collected clinical data, performed histological analyses and evaluated IHC results; IK collected tissue samples; LK carried out bioinformatic analyses and revised the manuscript; LB and KS helped with the methodological aspects and revised the manuscript; JS contributed to the final coherence of text; PB conceived the study and revised the manuscript.

Corresponding author

Correspondence to Petr Beneš.

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Conflict of interest

The authors declare that they have no competing interest.

Ethical approval

Clinical study was approved by the Ethics Committee of the University Hospital Brno (01-280617/EK), Masaryk Memorial Cancer Institute (2017/1892/MOU), and Masaryk University (EKV-2017-056). Animal experiments were approved by Institutional Ethical Committees (Academy of Sciences of the Czech Republic and Masaryk University).

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Written informed consent was obtained from all patients or their guardians.

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Říhová, K., Dúcka, M., Zambo, I.S. et al. Transcription factor c-Myb: novel prognostic factor in osteosarcoma. Clin Exp Metastasis 39, 375–390 (2022). https://doi.org/10.1007/s10585-021-10145-4

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