Cyclin‐dependent kinase subunit2 (CKS2) promotes malignant phenotypes and epithelial‐mesenchymal transition‐like process in glioma by activating TGFβ/SMAD signaling

Abstract

Background: Gliomas are a group of primary intracranial tumors with high morbidity and mortality. The previous researches indicated a crucial role of CKS2 (cyclin-dependent kinases regulatory subunit 2) in hepatocellular carcinoma and breast cancer; however, little is known about the molecular mechanism of CKS2 in the tumorigenesis and epithelial-mesenchymal transition-like (EMT) process in glioma.Methods: Datasets for bioinformatics analysis were obtained from the GEO, TCGA and CGGA databases. qRT-PCR, western blotting (WB), and immunohistochemistry (IHC) assays were used to investigate the expression patterns of CKS2 among glioma and brain tissues. Glioma cells were transfected with small interfering RNA/overexpression plasmid against CKS2, then clone formation assay, CCK-8, wound healing, Transwell assay, and flow cytometry were performed to detect changes in cell viability, invasiveness, and the apoptosis rate. Markers of cell invasion, apoptosis, EMT and TGFβ/SMAD signaling were evaluated by WB and immunofluorescence (IF) assays. Results:We found that CKS2 overexpression correlates with poor prognosis in human glioma and knockdown of CKS2 could inhibit cell proliferation, migration, invasion, and induced apoptosis in glioma cells. Besides, we also found that knockdown of CKS2 could reverse the EMT process via modulating EMT-related molecules. Glioma cells with overexpression of CKS2 were constructed to confirmed the fact that CKS2 induced nucleocytoplasmic translocation of SMAD2/3 and activated TGFβ/SMAD pathway, then upregulated its downstream targets expression, while inhibition of TGFβ/SMAD (by TGFβ inhibitor LY2157299 or SMAD4 siRNA) could reverse the tumor-promoting effects and malignant phenotype caused by CKS2 overexpression.

Prognostic significance of cyclin-dependent kinase subunit 2 (CKS2) in malignant tumours: a meta-analysis and bioinformatic analysis

“…The article screening process is shown in figure 1. Of the 13 included articles,8 9 19–29 10 were from China, 2 were from Japan and 1 was from South Korea. Their sample size ranged from 38 to 345, with a mean of 103.7.…”

Heterogeneity of cancer-associated fibroblasts in head and neck squamous cell carcinoma

“…Our study incorporated data from TCGA and revealed that only CKS2+ iCAFs exhibited significant prognostic relevance ( P <0.05). CKS2 protein binds to the catalytic subunit of cyclin-dependent kinases, thereby activating their biological functions [ 41 , 42 ]. Gene Ontology (GO) annotations associated with CKS2 include cyclin-dependent protein serine/threonine kinase regulator activity.…”

Single-Cell RNA Sequencing: Opportunities and Challenges for Studies on Corneal Biology in Health and Disease

“…Ligocki et al identified pathways involved in proliferation such as the WNT [ 56 ], p53, p63 [ 57 ], and c-Myc pathways and were predicted to be important for limbal stem cells and limbal progenitor cells. Furthermore, the novel genes CKS2 , STMN1 , UBE2C , and E2F8 , which encode transcription factors generally known to be involved in cell proliferation [ 58 , 59 , 60 , 61 , 62 ], were reported and were hypothesized to promote proliferation of TACs in the studies by Ligocki et al, Català et al, and Li et al In the studies by Collin et al and Gautam et al, the NF-κB pathway genes REL , RELA , and RELB were shown to be expressed in cell states of the limbal region [ 29 , 30 ]. A recent study showed that RELA is involved in corneal regeneration and maintenance through the retinoic acid pathway, which is implicated in age-related corneal damage [ 63 ].…”