Abstract
Non-muscle-invasive bladder cancer (NMIBC) is a common disease with a high recurrence rate requiring lifetime surveillance. Although NMIBC is not life-threatening, it can progress to muscle-invasive bladder cancer (MIBC), a lethal form of the disease. The management of the two diseases differs, and patients with MIBC require aggressive treatments such as chemotherapy and radical cystectomy. NMIBC patients at a high risk of progression benefit from early immediate cystectomy. Thus, identifying concordant markers for accurate risk stratification is critical to predict the prognosis of NMIBC. Candidate genetic biomarkers associated with NMIBC prognosis were screened by RNA-sequencing of 24 tissue samples, including 16 NMIBC and eight normal controls, and by microarray analysis (GSE13507). Lastly, we selected and investigated a mitotic checkpoint serine/threonine kinase, BUB1, that regulates chromosome segregation during the cell cycle. BUB1 gene expression was tested in 86 NMIBC samples and 15 controls by real-time qPCR. The performance of BUB1 as a prognostic biomarker for NMIBC was validated in the internal Chungbuk cohort (GSE13507) and the external UROMOL cohort (E-MTAB-4321). BUB1 expression was higher in NMIBC patients than in normal controls (p < 0.05), and the overexpression of BUB1 was correlated with NMIBC progression (log-rank test, p = 0.007). In in vitro analyses, BUB1 promoted the proliferation of bladder cancer cells by accelerating the G2/M transition of the cell cycle. Conclusively, BUB1 modulates the G2/M transition to promote the proliferation of bladder cancer cells, suggesting that it could serve as a prognostic marker in NMIBC.
Highlights
BUB1 is downregulated in sarcomas, lymphomas, and lung tumors, whereas BUB1 upregulation is associated with liver cancer [6]
The heatmap depicted 1178 differentially expressed genes (DEGs) with 270 upregulated and 908 downregulated genes in Non-muscle-invasive bladder cancer (NMIBC) compared with normal adjacent tissue (NAT) (FDR < 0.01, >2-fold differences in expression; Supplementary Figure S1A)
Gene ontology (GO) analysis in biological processes revealed the functional profiles of DEGs, indicating that genes with higher transcription levels in NMIBC than in NAT were enriched in the following GO terms: cell division, DNA conformation change, regulation of cell cycle progression, and DNA repair
Summary
Aneuploidy is the presence of an aberrant number of chromosomes in a cell. It is the result of chromosomal instability, a hallmark of cancer [1]. Defects in the mitotic spindle checkpoint contribute to chromosome instability and aneuploidy in several cancers [2,3,4]. Budding uninhibited by benzimidazole 1 (BUB1) is a well-characterized component of the spindle checkpoint that has versatile and distinct functions during the cell cycle [5]. BUB1 plays a role in oncogenesis, as indicated by the occurrence of BUB1 mutations, as well as differential BUB1 gene and protein expression in cancer tissues and cell lines [5]. In bladder cancer (BCa), weighted gene co-expression network analysis showed that BUB1 is upregulated in high-grade
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