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CDK12 activates MYC to repress miR-28-5p/EZH2 and amplifies tonic BCR signaling to promote the development of diffuse large B-cell lymphoma

Cancer Gene Therapy volume 29, pages 1207–1216 (2022)Cite this article

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Abstract

Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase that participates in various cellular processes. However, its regulatory role in the progression of diffuse large B-cell lymphoma (DLBCL), which is the most prevalent subtype of non-Hodgkin lymphoma (NHL), is still elusive and controversial.The expression of CDK12 was detected by immunohistochemistry (IHC), RT-qPCR was performed to detect miR-28-5p expression of OCI-LY3 and SU-DHL-4 cells. MTT and soft agarose colony formation assays were used to detect cell proliferation. The cell apoptosis was determined by flow cytometry. The protein expressions changes of MYC, EZH2 and the biomarkers of BCR signaling were also detected. A subcutaneous transplantation tumor model of OCI-LY3 cells in nude mice was established to evaluate anticarcinogenic activities of CDK12 knockdown. Elevated expression of CDK12 was observed while miR-28-5p was downregulated in DLBCL tissues. CDK12 knockdown or miR-28-5p overexpression could inhibit proliferation and promote apoptosis of DLBCL cells. miR-28-5p inhibition could reverse the effect of CDK12 knockdown on proliferation and apoptosis of DLBCL cells. In addition, CDK12 knockdown could inhibit DLBCL tumor growth in the mice model. CDK12 activated MYC to repress miR-28-5p/EZH2 and amplified tonic BCR signaling to promote the development of DLBCL, which might provide potential therapeutic targets for future therapeutic intervention in DLBCL.

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Fig. 1: CDK12 was upregulated and miR-28-5p was downregulated in DLBCL tissues.
Fig. 2: CDK12 knockdown promoted apoptosis and inhibited the proliferation of DLBCL cells.
Fig. 3: MYC knockdown promoted apoptosis and inhibited the proliferation of DLBCL cells.
Fig. 4: miR-28-5p overexpression inhibited proliferation and promoted apoptosis of DLBCL cells.
Fig. 5: CDK12 regulated proliferation and apoptosis of DLBCL cells through miR-28-5p/EZH2/BCR signaling pathway.
Fig. 6: CDK12 knockdown inhibited DLBCL tumor growth in vivo.

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Funding

This word was supported by Research Fund of Anhui Institute of translational medicine (No. 2021zhyx-C39), the Anhui Medical University 2020 School Research Fund (No. 2020xkj163).

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Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230000, Anhui Province, China

    Qin-Hua Liu, Guan-Rong Dai, Lin Wang, Li-Li Li & Rui-Xiang Xia

  2. Laboratory of Pathogenic Microbiology and Immunology, Anhui Medical University, Hefei, 230032, Anhui Province, China

    Xiao-Nan Wang

  3. Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230000, Anhui Province, China

    Zheng-Sheng Wu

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Contributions

XRX: Funding and concept provision; LQH: Experimental operation; DGR: Assist in the experiment, writing the first draft of the manuscript; WXN: Data analysis; LLL: Project management; WZS: Manuscript review and revision. All authors have read and approved the final version of this manuscript to be published.

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Correspondence to Rui-Xiang Xia.

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Ethics

This study was approved by the Ethics Committee of Anhui Medical University. Informed written consent was obtained from all patients according to the Declaration of Helsinki. All procedures were in line with the most recent specifications of the National Research Council (US) Committee for the Care and Use of Laboratory Animals (2011).

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Liu, QH., Dai, GR., Wang, XN. et al. CDK12 activates MYC to repress miR-28-5p/EZH2 and amplifies tonic BCR signaling to promote the development of diffuse large B-cell lymphoma. Cancer Gene Ther 29, 1207–1216 (2022). https://doi.org/10.1038/s41417-021-00415-4

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