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. 2019 Dec 23;12(1):198.
doi: 10.1186/s12920-019-0645-x.

CDK1 and CCNB1 as potential diagnostic markers of rhabdomyosarcoma: validation following bioinformatics analysis

Qianru Li  1 , Liang Zhang  1   2 , Jinfang Jiang  1 , Yangyang Zhang  1 , Xiaomeng Wang  1 , Qiaochu Zhang  1 , Yang Wang  1 , Chunxia Liu  3 , Feng Li  4   5
Affiliations

CDK1 and CCNB1 as potential diagnostic markers of rhabdomyosarcoma: validation following bioinformatics analysis

Qianru Li et al. BMC Med Genomics. .

Abstract

Background: Rhabdomyosarcoma (RMS), a common soft-tissue malignancy in pediatrics, presents high invasiveness and mortality. However, besides known changes in the PAX3/7-FOXO1 fusion gene in alveolar RMS, the molecular mechanisms of the disease remain incompletely understood. The purpose of the study is to recognize potential biomarkers related with RMS and analyse their molecular mechanism, diagnosis and prognostic significance.

Methods: The Gene Expression Omnibus was used to search the RMS and normal striated muscle data sets. Differentially expressed genes (DEGs) were filtered using R software. The DAVID has become accustomed to performing functional annotations and pathway analysis on DEGs. The protein interaction was constructed and further processed by the STRING tool and Cytoscape software. Kaplan-Meier was used to estimate the effect of hub genes on the ending of sarcoma sufferers, and the expression of these genes in RMS was proved by real-time polymerase chain reaction (RT-PCR). Finally, the expression of CDK1 and CCNB1 in RMS was validated by immunohistochemistry (IHC).

Results: A total of 1932 DEGs were obtained, amongst which 1505 were up-regulated and 427were down-regulated. Up-regulated genes were largely enriched in the cell cycle, ECM-receptor interaction, PI3K/Akt and p53 pathways, whilst down-regulated genes were primarily enriched in the muscle contraction process. CDK1, CCNB1, CDC20, CCNB2, AURKB, MAD2L1, HIST2H2BE, CENPE, KIF2C and PCNA were identified as hub genes by Cytoscape analyses. Survival analysis showed that, except for HIST2H2BE, the other hub genes were highly expressed and related to poor prognosis in sarcoma. RT-PCR validation showed that CDK1, CCNB1, CDC20, CENPE and HIST2H2BE were significantly differential expression in RMS compared to the normal control. IHC revealed that the expression of CDK1 (28/32, 87.5%) and CCNB1 (26/32, 81.25%) were notably higher in RMS than normal controls (1/9, 11.1%; 0/9, 0%). Moreover, the CCNB1 was associated with the age and location of the patient's onset.

Conclusions: These results show that these hub genes, especially CDK1 and CCNB1, may be potential diagnostic biomarkers for RMS and provide a new perspective for the pathogenesis of RMS.

Keywords: Bioinformatics analysis; CCNB1; CDK1; Diagnosis; Hub genes; Rhabdomyosarcoma.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Volcanic diagram of DEGs. Red represents DEGs with fold change > 2, and black represents DEGs with fold change < 2
Fig. 2
Fig. 2
Top 10 hub genes identified in CytoHubba plug-in for DEGs from RMS and normal specimens. a Red indicates high enrichment, and yellow indicates low enrichment. b Degree and GO term of the hub genes
Fig. 3
Fig. 3
Pheatmap of the 10 hub genes. Red: up-regulation; Green: down-regulation
Fig. 4
Fig. 4
Top 6 modules with enrichment pathways identified from PPI of DEGs. a Module 1; b Enrichment of Module 1; c Module 2; d Enrichment of Module 2; e Module 3; f Enrichment of Module 3; g Module 4; h Enrichment of Module 4; i Module 5; j Enrichment of Module 5; k Module 6; l Enrichment of Module 6. Red nodes were up-regulated genes, green nodes were down-regulated genes, and gray nodes were interactions between nodes
Fig. 5
Fig. 5
Kaplan–Meier plotter of 9 hub genes in sarcoma specimens. Overall survival (OS) by low and high CDK1, CCNB1, CDC20, CCNB2, AURKB, MAD2L1, CENPE, KIF2C, and PCNA expression
Fig. 6
Fig. 6
Validation of 10 hub genes by RT-PCR. mRNA expression levels of 10 hub genes were detected in RMS patient tissue and normal striated muscle tissue. Each point represents an individual subject. *p < 0.05; **p < 0.01
Fig. 7
Fig. 7
Immunohistochemical staining of CDK1and CCNB1 expression in rhabdomyosarcoma and normal muscle tissues. Immunohistochemical staining for CDK1 demonstrated strong nuclear expression in RMS. a-c RMS (× 100); d Normal (× 100). Immunohistochemical staining for CCNB1 demonstrated nuclear or cytoplasm expression in RMS. e-g RMS (× 100); h Normal (× 100)
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