Abstract
Urothelial carcinoma (UC) occurs in the upper urinary tract (UTUC) and the urinary bladder (UBUC). The molecular pathogenesis of UC has not been fully elucidated. Through data mining of a published transcriptome of UBUC (GSE31684), we identified Minichromosome Maintenance Complex Component 2 (MCM2) and MCM10 as the two most significantly upregulated genes in UC progression among the MCM gene family, the key factors for the initiation of DNA replication. To validate the clinical significance of MCM2 and MCM10, immunohistochemistry, evaluated by H-score, was used in a pilot study of 50 UTUC and 50 UBUC samples. Only a high expression level of MCM10 predicted worse disease-specific survival (DSS) and inferior metastasis-free survival (MeFS) for both UTUC and UBUC. Correspondingly, evaluation of MCM10 mRNA expression in 36 UTUCs and 30 UBUCs showed significantly upregulated levels in high stage UC, suggesting its role in tumor progression. Evaluation of 340 UTUC and 296 UBUC tissue samples, respectively, demonstrated that high MCM10 immunoexpression was significantly associated with advanced primary tumors, nodal status, and the presence of vascular invasion in both groups of UCs. In multivariate Cox regression analyses, adjusted for standard clinicopathological features, MCM10 overexpression was independently associated with DSS (UTUC hazard ratio [HR]=2.401, P = 0.013; UBUC HR=4.323, P=0.001) and with MeFS (UTUC HR=3.294, P<0.001; UBUC HR=1.972, P=0.015). In vitro, knockdown of MCM10 gene significantly suppressed cell proliferation in both J82 and TCCSUP cells. In conclusion, MCM10 overexpression was associated with unfavorable clinicopathological characteristics and independent negative prognostic effects, justifying its potential theranostic value in UC.