MCM10 overexpression implicates adverse prognosis in urothelial carcinoma

// Wei-Ming Li 1, 2, 3, 4 , Chun-Nung Huang 2, 3 , Hung-Lung Ke 2, 3 , Ching-Chia Li 2, 3, 5 , Yu-Ching Wei 6 , Hsin-Chih Yeh 2, 3, 5 , Lin-Li Chang 1, 7 , Chun-Hsiung Huang 1, 2, 3 , Peir-In Liang 8 , Bi-Wen Yeh 2, 3 , Ti-Chun Chan 9 , Chien-Feng Li 9, 10, 11, 12, 13 , Wen-Jeng Wu 1, 2, 3, 5, 14, 15, 16 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 3 Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan 5 Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan 6 Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan 7 Department of Microbiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 8 Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 9 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 10 Departments of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan 11 National Cancer Research Institute, National Health Research Institutes, Tainan, Taiwan 12 Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 13 Department of Internal Medicine and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 14 Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan 15 Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan 16 Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan Correspondence to: Chien-Feng Li, email: angelo.p@yahoo.com.tw Wen-Jeng Wu, email: wejewu@kmu.edu.tw Keywords: urothelial carcinoma, transcriptome, MCM10, prognosis Received: July 20, 2016      Accepted: October 12, 2016      Published: October 21, 2016 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.