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

Introduction

Cancer, a leading cause of mortality worldwide, is fundamentally driven by aberrant cell proliferation—a process governed by the meticulous regulation of the cell division cycle.1 2 The fidelity of this cycle is vital for cell survival and proliferation, ensuring orderly growth, DNA replication and cell division.3 A complex regulatory network of cell cycle proteins ensures the seamless sequential repetition of phases in the cell division cycle.3 However, disruptions within this network can lead to the uncontrolled cell proliferation characteristic of cancerous growths. Understanding the molecular intricacies of this regulation is crucial since it holds the key to unlocking novel therapeutic targets and prognostic markers in oncology.

The cyclin-dependent kinase (CDK) subunits are central to cell cycle regulation, playing an integral role in modulating various phases in the cell division process.4 Among them, CDK subunit 2 (CKS2) has emerged as a protein of significant interest due to its critical involvement in the G2/M transition of the cell cycle.5 Beyond its role in cell cycle regulation, CKS2 is implicated in various physiological processes, including mitosis, cellular differentiation and cell proliferation.6 This multifaceted involvement underscores the potential of CKS2 as a key player in cancer pathophysiology.

Recent scientific studies have revealed that CKS2 is differentially overexpressed in multiple malignancies, including non-small-cell lung cancer, gastric cancer and glioma.7–9 This differential expression is not merely a consequence of but is closely associated with tumour progression and aggressiveness.10 Despite these revelations, the specific physiological roles and detailed molecular mechanisms by which CKS2 influences tumour cell proliferation remain largely unknown. Filling this knowledge gap is essential since it could facilitate the development of targeted therapies and enable CKS2’s use as a prognostic marker. Consequently, there is an urgent need for a comprehensive synthesis of the available data to elucidate the clinical relevance of CKS2 in oncology.

Given the critical role of CKS2 in cancer biology, this study pioneers a dual approach, combining a meta-analysis with bioinformatic analysis, to determine the prognostic significance of CKS2 in malignant tumours. This study is not merely academic; it is a clarion call to validate the prognostic potential of CKS2, understand its clinical implications and pave the way for its integration into personalised cancer care. By unravelling the correlation between CKS2 expression levels and various cancer prognostic factors, such as tumour stage, differentiation, lymph node metastasis and distant metastasis, this study seeks to establish CKS2 as a prognostic marker, setting the stage for its potential clinical use in personalised cancer care.

Discussion

The regulation of the cell division cycle is essential for cell survival and proliferation, and the sequential repetition of the phases in the cell division cycle is achieved through a complex regulatory network of cell cycle proteins.4 Therefore, tumours are caused by aberrant cell proliferation due to disruptions in cell cycle regulation.3 The CKS family comprises a group of small proteins that play important roles in regulating the cell division cycle.6 Both CKS1 and CKS2 are reportedly involved in regulating cell proliferation, playing distinct roles in different cell cycle phases.30 A component essential for the Skp, Cullin, F-box containing complex including S-phase kinase-associated protein 2 (SCFSkp2)-mediated degradation of p27 ubiquitination, CKS1 is mainly involved in regulating the G1/S transition of the cell cycle, whereas CKS2 is essential for the G2/M transition.31 32 CKS2 is also involved in regulating several physiological processes, including mitosis, cellular differentiation and cell proliferation. Recent studies have shown that CKS2 is differentially overexpressed in several cancer types, and this differential expression is closely associated with the progression of various cancers, including prostate cancer, nasopharyngeal carcinoma and glioma.33–36 CKS2 promotes cancer cell proliferation by regulating cell cycle proteins, including cyclin A, cyclin B1 (CCNB1) and CDK1.9 Nonetheless, the specific physiological roles of CKS2 and the detailed molecular mechanisms underlying its involvement in tumour cell proliferation remain largely unknown.

This is the first meta-analysis to integrate the outcomes of existing studies on CKS2 to further validate its potential prognostic value in tumours. It showed that a high CKS2 expression is unfavourable for survival in various cancers. High CKS2 expression correlated with patients’ tumour stage, the degree of tumour differentiation, lymph node metastasis and distant metastasis, further underscoring the critical correlation between high CKS2 expression and poor prognosis in patients with cancer. Bioinformatic analysis revealed significant overexpression of CKS2 in various cancers, consistent with the findings of several other studies, further solidifying the idea that CKS2 plays a critical role in different cancer types. In addition, it indicated that elevated CKS2 expression was significantly associated with worse OS in patients with glioma, liver hepatocellular carcinoma and lung adenocarcinoma. This finding is consistent with Yu et al,7 who also reported that high CKS2 expression was associated with reduced survival in patients with glioma. Similarly, Zhi et al37 found that increased CKS2 expression was a marker of poor prognosis in patients with hepatocellular carcinoma. These corroborative findings from diverse cancer types suggest that CKS2 might have a universal role in cancer biology, making it a promising candidate for further research and clinical application.

The clinical implications of our findings extend beyond mere prognostication. The clinical utility of this study lies in its potential to transform current oncological practices. By establishing CKS2 as a prognostic marker, this research provides a foundation for personalised medicine approaches in cancer care. Clinicians could use CKS2 expression levels as a biomarker to stratify patients based on their prognostic risk, enabling more tailored and potentially effective treatment strategies. For example, patients with high CKS2 expression might benefit from more aggressive treatment regimens or closer monitoring, while those with lower CKS2 expression could avoid excessive treatment. Furthermore, CKS2’s role in cell cycle regulation presents an opportunity for targeted therapies. CKS2 inhibitors could be developed as novel anticancer agents, potentially offering new treatment avenues for patients currently with limited options. Additionally, the early detection of CKS2 overexpression could facilitate the diagnosis of aggressive cancer subtypes, leading to earlier intervention and improved patient outcomes. Overall, our study underscores the importance of biomarker research in advancing precision oncology and improving cancer prognosis. Despite these promising prospects, there remains a long way to go. Further research, clinical trials and the development of targeted therapies are essential to fully realise the potential of CKS2 as a cornerstone in cancer diagnosis, treatment and management.

Our study observed a significant correlation between CKS2 expression levels and the prognosis of patients with malignant tumours, consistent with recent research. However, it had the following limitations. First, the included studies only represented 11 cancer types, primarily digestive malignancies. Consequently, it may not comprehensively represent the full spectrum of malignancies, and the observed associations should be interpreted cautiously and may not be universally prognostic. Second, no clinical trials were identified in our search, which is a significant limitation. The studies included in our analysis were retrospective, so their evidence was weak due to the lack of randomised controlled trials. Consequently, the findings of our meta-analysis are based on associations and correlations observed in cohort studies rather than definitive causation. Third, the included patients with cancer were clinically heterogeneous, with different tumour stages, surgical approaches and adjuvant treatments. Fourth, inconsistent measurement procedures and criteria for quantifying CKS2 expression levels may have increased heterogeneity in our study, leading to measurement bias. Fifth, the corresponding data obtained from Kaplan-Meier curves may have contained errors, possibly impacting our final results. Sixth, our study had some heterogeneity and bias that could not be avoided altogether. Therefore, while our study provides valuable insights into CKS2’s role in cancer prognosis, prospective studies with standardised assessment methods are imperative to validate our findings and explore the therapeutic potential of CKS2 in cancer management. Furthermore, in this study, we focused primarily on the expression levels and prognostic significance of CKS2 in various malignancies. A strategic decision was made to concentrate on gene expression rather than epigenetic modifications, such as gene methylation. This choice was driven by our objective to provide a streamlined examination of CKS2’s role within a specific scope, aiming for clear insights into its expression patterns and implications in cancer. Future studies may involve a comparative analysis of gene expression and methylation patterns, potentially offering novel insights into cancer biology and aiding in the development of targeted therapeutic strategies.

In conclusion, high CKS2 expression may result in a reduced OS in patients with cancer and correlate with their tumour stage, degree of tumour differentiation, lymph node metastasis and distant metastasis. Therefore, CKS2 could be a potential prognostic marker for various cancers. Regarding future perspectives, the prognostic value of CKS2 should be further validated in multiple cancers using larger sample sizes, broader population sources and standardised clinical trials.

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