Identification of CDKL3 as a Critical Promoter in Development of Glioma Through Regulation of RRM2 and JNK Signaling Pathway

Abstract

Background: Glioma is one of the most commonly diagnosed intracranial malignant tumors. The molecular mechanism underlying the development of glioma is still largely unknown. Methods: We found CDKL3 as a potential promoter in glioma, by RNA high-throughput sequencing. To explore its biological characteristic, potential molecular mechanism, and clinical relevance in glioblastoma patients, we performed several in-vitro and in-vivo models, as well as human tissues. Findings: In this study, we present the first report concerning the role of CDKL3 in the development and prognosis of glioma. It is demonstrated that CDKL3 was up-regulated in glioma tissues and independently predicted poor prognosis of glioblastoma patients. Silencing CDKL3 in glioma cells could inhibit cell proliferation and migration, induce cell apoptosis and cell cycle arrest, while the over-expression of CDKL3 promoted cell proliferation. The in vivo experiments also indicated that knockdown of CDKL3 significantly suppressed tumor growth of glioma. Gene expression profiling of CDKL3 knockdown U87 cells identified RRM2 as a potential target of CDKL3, which was proved to have direct interaction with CDKL3. Given similar effects on glioma development with CDKL3, knockdown of RRM2 could rescue the effects of CDKL3 over-expression on glioma cells. Moreover, knockdown of CDKL3 or RRM2 suppressed the activity of JNK signaling, while CDKL3 over-expression exhibited contrary effects. Interpretation: Our results identified CDKL3 as a tumor promotor for glioma, probably through the regulation of RRM2 and activation of the JNK signaling pathway, highlighting the significance of CDKL3 as a promising therapeutic target of glioma. Funding Statement: This work was financially supported by the National Natural Science Foundation of China (No.81472354). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: The Ethics Committee of the Changzheng Hospital Biomedical Research Department provided ethical approval(2018SL020), and informed consent for collecting and preserving samples and details was obtained from each patient. Animal studies were approved by the Ethical Committee of Naval Medical University and were carried out following guidelines for animal care and protection and protocols.