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Cyclin-dependent kinase 12 (CDK12) in chordoma: prognostic and therapeutic value

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Abstract

Purpose

To determine the cyclin-dependent kinase 12 (CDK12) expression in chordoma patient tissues and cell lines, its correlation with oncologic outcomes, and its function in chordoma cell proliferation.

Methods

A chordoma tissue microarray was constructed from fifty-six patient specimens and examined by immunohistochemistry to measure CDK12 expression and its correlation to patient clinical characteristics and survival. CDK12 expression in chordoma cell lines and patient tissues was evaluated via western blot. CDK12 specific small interfering RNA (siRNA) was applied to determine whether its inhibition attenuated chordoma cell growth and proliferation.

Results

CDK12 was expressed in the majority of chordoma specimens, with notably higher expression in patients with recurrent or metastatic disease. High CDK12 expression was an independent prognostic predictor for shorter overall and progression-free survival in chordoma by univariate and multivariate analysis. Western blot analysis revealed that CDK12 was also highly expressed in chordoma cell lines, with CDK12 specific small interfering RNA (siRNA) mediated knockdown decreasing proliferation and inducing apoptosis. Mechanistically, inhibition of CDK12 decreased phosphorylation of RNA polymerase II (RNAP II) and the anti-apoptotic proteins Survivin and Mcl-1.

Conclusion

High expression of CDK12 is an independent predictor of poor prognosis in chordoma. Inhibition of CDK12 significantly decreased chordoma cell proliferation and induced apoptosis. Our results support CDK12 as a novel prognostic biomarker and therapeutic target in chordoma.

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Acknowledgement

This work was supported, in part, by the Department of Orthopaedic Surgery at UCLA.

Funding

There is no financial support for this study.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Sarcoma Biology Laboratory, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young. Dr. South, Los Angeles, CA, 90095, USA

    Pichaya Thanindratarn, Dylan C. Dean, Wenlong Feng, Ran Wei, Francis J. Hornicek & Zhenfeng Duan

  2. Department of Orthopedic Surgery, Chulabhorn Hospital, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand

    Pichaya Thanindratarn

  3. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Wenlong Feng

  4. Musculoskeletal Tumor Center, Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People’s Hospital, Beijing, China

    Ran Wei

  5. Department of Pathology, University of California, Los Angeles, CA, USA

    Scott D. Nelson

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  1. Pichaya Thanindratarn
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  2. Dylan C. Dean
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Correspondence to Zhenfeng Duan.

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Thanindratarn, P., Dean, D.C., Feng, W. et al. Cyclin-dependent kinase 12 (CDK12) in chordoma: prognostic and therapeutic value. Eur Spine J 29, 3214–3228 (2020). https://doi.org/10.1007/s00586-020-06543-z

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