Abstract

Introduction: Osteosarcoma (OS) is the most prevalent kind of bone cancer, but the tumorigenesis and underlying molecular drivers of OS remain unknown. The instability of the cell cycle regulation system, which leads to uncontrolled cell proliferation, is a typical characteristic of carcinogenesis. This study aimed to investigate the expression of SKP2 in human OS and assessed its prognostic value in OS patients. Methods: Three gene expression profile datasets GSE28424, GSE42352 and GSE21257 were obtained from the GEO database. The Wilcoxon rank-sum test was performed to evaluate the differential expression of the SKP2 gene between the OS and the control groups in the GSE28424 and GSE42352 datasets, and the correlation between SKP2 expression and Huvos grade was analysed in the GSE21257 dataset. Subsequently, PPI network, GO and KEGG analyses were constructed. Furthermore, survival analysis between high SKP2 expression group and low SKP2 expression group was performed using the Kaplan–Meier method and log-rank test. In addition, the UALCAN database was used to investigate the association between SKP2 expression and sarcoma. Results: The expression level of SKP2 in OS cells was significantly higher than that in normal bones and mesenchymal stem cell samples. Furthermore, the level of SKP2 expression was observed to decrease as Huvos grade increased. The PPI network was established, and the top ten SKP2-related genes were identified, including CDKs (1, 2, 4, and 6), Cyclin A1-2, E1-2, D1, and CDKN1A. The survival analysis showed that the elevated SKP2 expression level was significantly related to the overall survival of OS patients. Conclusion: Our work adds to our knowledge of SKP2's function in OS and suggests that it might be used as a therapeutic target in the future.

Highlights

  • Osteosarcoma (OS) is the most prevalent kind of bone cancer, but the tumorigenesis and underlying molecular drivers of OS remain unknown

  • The instability of the cell cycle regulation system, which leads to uncontrolled cell proliferation, is a typical characteristic of carcinogenesis, and a variety of regulatory factors in the cell cycle are degraded through the ubiquitin-proteasome pathway

  • The expression difference of S-Phase Kinase-Associated Protein 2 (SKP2) between the tumour tissues of sarcoma and the corresponding normal tissues in the The Cancer Genome Atlas (TCGA) project was evaluated through the UALCAN web portal (Figure 1 C), and it was statistically significant (P < 0.001)

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Summary

Introduction

Osteosarcoma (OS) is the most prevalent kind of bone cancer, but the tumorigenesis and underlying molecular drivers of OS remain unknown. The PPI network was established, and the top ten SKP2-related genes were identified, including CDKs (1, 2, 4, and 6), Cyclin A1-2, E1-2, D1, and CDKN1A. SKP2 (S-Phase Kinase-Associated Protein 2), named FBXL1 (F-Box/LRR-Repeat Protein 1) or p45 (CDK2/cyclin A-associated protein p45), encodes for a 45 kDa protein that belongs to the F-box family, it could ubiquitinate and degrade numerous tumour suppressor proteins such as p27, and so plays a crucial role in regulating the cell cycle. It was found that SKP2 was highly expressed and played a major role in carcinogenesis in numerous kinds of malignancies, including soft tissue sarcomas (STS) 7, breast cancer 8, hepatocellular carcinoma (HCC) 9, pancreatic ductal adenocarcinoma (PDAC) 10, astrocytic gliomas 11.

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