MCM10過度表現對於尿路上皮癌病人預後之影響
李威明1, 2, 3,4、吳文正1,4,5、李經家1,4,5、柯宏龍1,4、韋又菁6、葉信志1,4,5、
李健逢7、黃俊農1,4、黃俊雄1,4
高雄醫學大學附設中和紀念醫院泌尿部1; 高雄醫學大學醫學研究所2; 衛生福利部屏東醫院3,; 高雄醫學大學醫學系泌尿科4; 高雄市立大同醫院泌尿科5; 高雄市立大同醫院病理科6;奇美醫學中心病理科7
The impact of MCM10 overexpression in patients with urothelial carcinoma
Wei-Ming Li 1,2,3,4, Wen-Jeng Wu 1,4,5, Ching-Chia Li 1,4,5, Hung-Lung Ke 1,4, Yu-Ching Wei6, Hsin-Chin Yen1,4,5, Chien-Feng Li7, Chun-Nung Huang 1, 4, Chun-Hsiung Huang 1,4
1Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
3 Pingtung Hospital, Ministry of Health and Welfare, Executive Yuan, Pingtung, Taiwan
4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
5 Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
6 Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
7Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan
Purpose: Urothelial carcinomas (UC) of urinary bladder (UB) and upper urinary tract (UT) are heterogeneous diseases with high morbidity and mortality 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 10 (MCM10) as the most significantly upregulated gene in UC progression among the MCM gene family, the key factors for the initiation of DNA replication. We then analyzed MCM10 expression and association with clinicopathologic factors and survival in our well-characterized cohort of UCs.
Materials and Methods: We performed real-time reverse transcriptase-polymerase chain reaction assay to determine the MCM10 transcript level in 36 UTUCs and 30 UBUCs. Immunohistochemistry evaluated by H-score was used to determine MCM10 protein expression in 340 UTUCs and 295 UBUCs. In this retrospective study, MCM10 expression was correlated with clinicopathologic features and with disease-specific survival (DSS) and metastasis free survival (MeFS). The statistical significance was evaluated with univariate and multivariate analyses. We further elucidated the biologic function of MCM10 using RNA interference in MCM10-overexpressing UC cells.
Results: An increased MCM10 mRNA level was associated with higher pT stage in UTUC (P=0.001) and UBUC (P=0.004). High MCM10 expression was significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular and perineural invasion, and frequent mitoses. In multivariate Cox regression analyses, adjusted for standard clinicopathologic 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.
Conclusions: MCM10 overexpression is associated with aggressive tumor phenotype and unfavorable clinical outcome in UTUC and UBUC, suggesting it may serve as a novel prognostic and therapeutic target.