Identification of TYMS as a promoting factor of retroperitoneal liposarcoma progression: Bioinformatics analysis and biological evidence.

Abstract

Retroperitoneal liposarcoma (RLPS) is one of the most common types of retroperitoneal sarcomas, and has a high recurrence rate. There is an urgent need to further explore its pathogenesis and develop more effective treatment strategies. The aim of the present study was to identify potential driver genes of RLPS through bioinformatics analysis and molecular biology to elucidate potential targets that are suitable for further analysis for the treatment of RLPS. Differentially expressed genes (DEGs) between liposarcoma and normal fatty (NF) tissues were identified based on microarray data through bioinformatics analysis, and thymidylate synthase (TYMS) was selected from the DEGs, based on high content screening (HCS). TYMS expression was evaluated in RLPS tumor tissues and cell lines. A total of 21 RLPS tissues and 10 NF frozen tissues were used for reverse transcription‑quantitative PCR, and 47 RLPS formalin‑fixed specimens were used for immunohistochemical analysis. The effect of TYMS downregulation on cell proliferation, apoptosis, cell cycle progression, and cell migration and invasion were evaluated using lentivirus‑mediated short hairpin RNA. The underlying mechanisms of TYMS in RLPS were examined by protein microarray and verified by western blotting. A total of 855 DEGs were identified. TYMS knockdown had the most notable effect on the proliferative capacity of RLPS cells according to the HCS results. TYMS mRNA expression levels were higher in RLPS tissues compared with NF tissues (P<0.001). TYMS expression was higher in high‑grade RLPS tissues compared with low‑grade RLPS tissues (P=0.003). The patients with positive TYMS expression had a worse overall survival (OS) and disease‑free survival (DFS) compared with the patients with negative TYMS expression (OS, P=0.024; DFS, P=0.030). The knockdown of TYMS reduced proliferation, promoted apoptosis, facilitated cell cycle progression from G1 to S phase, and reduced cell migration and invasion of RLPS cells. Protein microarray analysis and western blotting showed that the Janus Kinase/Signal transducers and activators of transcription pathway was downregulated following TYMS knockdown. In conclusion, TYMS expression is upregulated in RLPS tissues, and downregulation of TYMS reduces RLPS progression.

• Authors: Sha Zhang, Liang Yan, Can Cui, Zhen Wang, Jianhui Wu, Min Zhao, Bin Dong, Xiaoya Guan, Xiuyun Tian, Chunyi Hao
• Journal: Oncology reports (Oncol Rep) Vol. 44 Issue 2 Pg. 565-576 (08 2020) ISSN: 1791-2431 [Electronic] Greece
• PMID: 32627015 (Publication Type: Journal Article)

Chemical References

• TYMS protein, human
• Thymidylate Synthase

Topics

• Adult
• Aged
• Apoptosis (genetics)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Computational Biology
• Datasets as Topic
• Disease Progression
• Disease-Free Survival
• Female
• G1 Phase Cell Cycle Checkpoints (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Liposarcoma (genetics, mortality, pathology)
• Male
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Retroperitoneal Neoplasms (genetics, mortality, pathology)
• Thymidylate Synthase (genetics, metabolism)
• Up-Regulation