NEK2 enhances malignancies of glioblastoma via NIK/NF-κB pathway

Abstract

Glioblastoma (GBM) is one of the most lethal primary brain tumor with a poor median survival less than 15 months. Despite the development of the clinical strategies over the decades, the outcomes for GBM patients remain dismal due to the strong proliferation and invasion ability and the acquired resistance to radiotherapy and chemotherapy. Therefore, developing new biomarkers and therapeutic strategies targeting GBM is in urgent need. In this study, gene expression datasets and relevant clinical information were extracted from public cancers/glioma datasets, including TCGA, GRAVENDEEL, REMBRANDT, and GILL datasets. Differentially expressed genes were analyzed and NEK2 was picked as a candidate gene for subsequent validation. Human tissue samples and corresponding data were collected from our center and detected by immunohistochemistry analysis. Molecular biological assays and in vivo xenograft transplantation were performed to confirm the bioinformatic findings. High-throughput RNA sequencing, followed by KEGG analysis, GSEA analysis and GO analysis were conducted to identify potential signaling pathways related to NEK2 expression. Subsequent mechanism assays were used to verify the relationship between NEK2 and NF-κB signaling. Overall, we identified that NEK2 is significantly upregulated in GBM and the higher expression of NEK2 exhibited a poorer prognosis. Functionally, NEK2 knockdown attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM while NEK2 overexpression promoted the GBM progression. Furthermore, High-throughput RNA sequencing and bioinformatics analysis indicated that NEK2 was positively related to the NF-κB signaling pathway in GBM. Mechanically, NEK2 activated the noncanonical NF-κB signaling pathway by phosphorylating NIK and increasing the activity and stability of NIK. In conclusion, NEK2 promoted the progression of GBM through activation of noncanonical NF-κB signaling, indicating that NEK2- NF-κB axis could be a potential drug target for GBM.

NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143

“…5 B). Based on reports NEK2 mediated the crosstalk of phosphorylation and ubiquitination on substrates [ 9 , 18 , 19 ], the combination of NEK2 and YAP1 should be proved to allow the occurrence of phosphorylation. It turned out that NEK2 was precipitated by YAP1-connect beads and vice versa, which became weaker in the Lv-shNEK2 group, confirming their physical contact in vitro (Fig.…”

Never in Mitosis Kinase 2 regulation of metabolism is required for neural differentiation

“…3). The loss of Nek2 was also reported to cause reduced proliferation in glioblastoma and medulloblastoma cell lines, however, this reduction was accompanied by increased apoptosis [29,30]. Another report also observed the reduced ability of Nek2-depleted cells to form spheroids (similar to EBs) in a hepatocellular carcinoma cell line [27].…”

“…Nek2, serving as a Gli1/2 target gene [22], also phosphorylates and stabilizes SUFU [23], placing it as negative regulator of the Hh pathway. Overexpression of Nek2 has also been linked to multiple Wnt-and Hh-associated cancers, including those causing brain malignancies [27][28][29][30][31][32].…”

The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest

“…Both cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM, Gibco, Carlsbad, USA) containing 10% heat-inactivated fetal bovine serum (FBS, ABW, Shanghai, China) and 1% penicillin/streptomycin (Gibco) at 37 °C in a humidified atmosphere of 5% CO 2 . Patient-derived primary GBM cell (GBM38 and GBM60) isolation and culture were performed according to the method described by Xiang et al [ 31 ]. Tumor tissues were obtained with the informed consent of patients and approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University.…”