Abstract
BackgroundHepatocellular carcinoma (HCC) was frequently considered as a kind of malignant tumor with a poor prognosis. Cyclin-dependent kinases (CDK) 4 was considered to be cell-cycle-related CDK gene. In this study, we explored the clinical significance of CDK4 in HCC patients.MethodsData of HCC patients were obtained from The Cancer Genome Atlas database (TCGA) and the Gene Expression Omnibus (GEO) database. Kaplan–Meier analysis and Cox regression model were performed to calculate median survival time (MST) and the hazard ration (HR), respectively. The joint-effect analysis and prognostic risk score model were constructed to demonstrate significance of prognosis-related genes. The differential expression of prognostic genes was further validated using reverse transcription-quantitative PCR (RT-qPCR) of 58 pairs of HCC samples.ResultsCDK1 and CDK4 were considered prognostic genes in TCGA and GSE14520 cohort. The result of joint-effect model indicated patients in CDK1 and CDK4 low expression groups had a better prognosis in TCGA (adjusted HR = 0.491; adjusted P = 0.003) and GSE14520 cohort (adjusted HR = 0.431; adjusted P = 0.002). Regarding Kaplan–Meier analysis, high expression of CDK1 and CDK4 was related to poor prognosis in both the TCGA (P < 0.001 and = 0.001 for CDK1 and CDK4, respectively) and the GSE14520 cohort (P = 0.006 and = 0.033 for CDK1 and CDK4, respectively). However, only CDK4 (P = 0.042) was validated in RT-qPCR experiment, while CDK1 (P = 0.075) was not.ConclusionHCC patients with high CDK4 expression have poor prognosis, and CDK4 could be a potential candidate diagnostic biomarker for HCC.
Highlights
Hepatocellular carcinoma (HCC) was frequently considered as a kind of malignant tumor with a poor prognosis
Bioinformatics analysis and correlation analysis The results of Gene Ontology (GO) analysis suggested that biological functions (Cellular component, Biological process, Molecular function) of CDK1-4, 6 were involved in regulation of cell cycle, serine/threonine protein kinase complex and protein serine/threonine kinase activity, etc. (Fig. 2A) The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated pathways involved in CDK1-4, 6 were enriched cell cycle, p53 signaling pathway, cellular senescence and PI3K-Akt signaling pathway (Fig. 2B and Additional files 1, 2: Figure S1-2) [35,36,37]
The protein–protein interaction (PPI) networks suggested that CDK1-4, 6 proteins were associated with Cyclins (CCN) family proteins, CDC20, CDKN1A and CKS1B (Fig. 3A)
Summary
Hepatocellular carcinoma (HCC) was frequently considered as a kind of malignant tumor with a poor prognosis. Cyclin-dependent kinases (CDK) 4 was considered to be cell-cycle-related CDK gene. We explored the clinical significance of CDK4 in HCC patients. The CDKs genes family play a vital role in cell division and modulating transcription [7]. A total of 21 genes in the CDKs gene family were divided into 11 subfamilies, of which CDK1 (CDK1, CDK2, CDK3), CDK4 (CDK4, CDK6) subfamily were considered to be cell-cycle-related subfamilies [7, 8]. Cell cycle regulators were frequently mutated in the tumor, including overexpression of CDKs [9]. The relationship between CDK1-4, 6 expression and the risk of HCC patients was rarely reported. This study aims to explore the role of CDK1-4, 6 expressions in HCC patients based on public cancer data
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