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NEK2 is a member of the never in mitosis A (NIMA)-related kinases family which is a kind of cyclin, playing an important role in the process of mitosis. It had been demonstrated that abnormal expression of NEK2 could promote tumorigenesis. At the same time, NEK2 exhibits elevated expression in a wide variety of human tumors. According the all above, NEK2 could become an important signal in diagnosis of cancer and a potential target in tumor therapy. In this paper, we will summarize the role of NEK2 in human cancer aiming at new strategies for cancer treatment.

Chemotherapy is an important treatment modality for osteosarcoma (OS), but the development of chemoresistance limits the therapeutic efficacy of OS and results in a poor prognosis. Thus, a better understanding of the mechanisms underlying chemoresistance in OS is essential. We previously demonstrated that COPS3/CSN3 (COP9 signalosome subunit 3) functions as an oncogene to promote OS cells lung metastasis, which is closely related to chemoresistance. Here, we showed that COPS3 was significantly upregulated in OS tissues with poor response to preoperative chemotherapy. Moreover, COPS3 depletion made OS cells more sensitive to cisplatin treatment in vitro and in vivo, implicating COPS3 as a driver of cisplatin resistance. Mechanistic investigations showed that COPS3 induced a cytoprotective macroautophagy/autophagy in response to cisplatin. Specifically, we identified FOXO3 as a critical target of COPS3, as high expression of COPS3 enhanced the nuclear abundance of FOXO3 and increased the expression of FOXO3-responsive genes, promoting autophagosome formation and maturation. In turn, FOXO3 regulated COPS3 levels by inhibiting ubiquitin-mediated degradation and attenuating SKP2-mediated COPS3 inhibition, cooperatively maintaining a high level of COPS3. In both COPS3-expressing OS cells and a murine xenograft model, inhibition of autophagy could also overcome resistance to cisplatin. Collectively, our results offer insights into the mechanisms of cisplatin resistance and suggest that targeting COPS3-mediated autophagy is a promising therapeutic strategy for overcoming the cisplatin resistance of OS. Abbreviations: 3-MA: 3-methyladenine; BECN1: beclin 1; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; COPS3/CSN3: COP9 signalosome subunit 3; CQ: chloroquine; DEGs: differentially expressed genes; FOXO3: forkhead box O3; GFP: green fluorescent protein; IC50: 50% inhibitory concentration; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; mRFP: monomeric red fluorescent protein; OS: osteosarcoma; PBS: phosphate-buffered saline; qRT-PCR: quantitative real-time PCR; RAB7: RAB7, member RAS oncogene family; RPS6KB1/p70S6K1: ribosomal protein S6 kinase B1; SEM: standard error of the mean; shRNA: short hairpin RNA; siRNA: small interfering RNA; SKP2: S-phase kinase associated protein 2; TEM: transmission electron microscopy; UPS: ubiquitin-proteasome system [ABSTRACT FROM AUTHOR]

Objectives: The fact that studies on anti‐programmed cell death 1 (PD‐1) or its relevant ligand 1 (PD‐L1) have yielded such few responses greatly decreases the confidence in immunotherapy with checkpoint inhibitors for advanced osteosarcoma. We intended to characterize the expression of various checkpoint molecules with immunohistochemistry in osteosarcoma specimens and analyzed the relationship of the expression of these checkpoint molecules with patients' clinical courses. Methods: This study was a retrospective non‐intervention study from August 1st 2017 to March 1st 2020. Immunohistochemistry for B7‐H3 (CD276, Cluster of Differentiation 276), CD47 (Cluster of Differentiation 47), PD‐L1 (programmed cell death ligand 1), TIM3 (mucin‐domain containing‐3), TGF‐β (TransformingGrowth Factor β), CXCR 4 (Chemokine Receptor 4), CD27 (Cluster of Differentiation 27), IDO1 (Indoleamine 2,3‐dioxygenase 1), KIRs (Killer cell Immunoglobulin‐like Receptors), and SDF‐1 (Stromal cell‐Derived Factor‐1) was performed on 35 resected osteosarcoma specimens. Patients progressed upon first‐line chemotherapy with evaluable lesions were qualified for this study, and their specimens previously stored in the pathological department repository would be retrieved for analysis. Associations between the immunohischemistry markers and clinicopathological variables and survival were evaluated by the χ2 displayed by cross‐table, Cox proportional hazards regression model, and Kaplan–Meier plots. Results: The positive rates of B7‐H3, CD47, PD‐L1, TIM3, and TGF‐β expression in this sample of 35 heavily treated osteosarcomas were 29% (10/35), 15% (5/35), 9% (3/35), 6% (2/35), and 6% (2/35), respectively, and diverse staining intensities were observed. Among these advanced patients, 15/35 (43%) had positive checkpoint expression, of which 33% (5/15) showed evidence of the co‐expression of more than one checkpoint molecule. We did not find any obvious correlation with clinicopathological characteristics and the positive expression of these molecules. Conclusions: The present study highlights that only a small subset of progressive osteosarcomas, which had been heavily‐treated, expressed tumor immune‐associated checkpoint molecules, of which B7‐H3 was the most positively expressed checkpoint and might be a promising target for further osteosarcoma investigation. [ABSTRACT FROM AUTHOR]