DDR2過度表現對於尿路上皮癌病人預後之影響
李威明1,2,3、吳文正1,3,5、柯宏龍1,3、李經家1,3、連培因4、韋又菁6、葉信志1,3,5、
李健逢7、黃俊農3,5、黃俊雄1,3
高雄醫學大學附設中和紀念醫院泌尿部1; 衛生福利部屏東醫院泌尿科2; 高雄醫學大學醫學系泌尿學科3; 高雄醫學大學附設中和紀念醫院病理部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; 奇美醫學中心病理部7
The Prognostic impact of DDr2 Overexpression in Patients with Urothelial Carcinoma
Wei-Ming Li 1,2,3, Peir-In Liang4, Wen-Jeng Wu 1,3,5, Ching-Chia Li 1,3, Hung-Lung Ke 1,3, Yu-Ching Wei6, Hsin-Chin Yen1,3,5, Chien-Feng Li7, Chun-Nung Huang 3,5, Chun-Hsiung Huang 1,3
1Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Department of Urology, Pingtung Hospital, Ministry of Health and Welfare, Executive Yuan, Pingtung, Taiwan
3 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
4Department of Pathology, Kaohsiung Medical University Hospital, 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 carcinoma (UC), a most common cancer from the urinary bladder (UB) and upper tract (UT), features complex gene expression and molecular interactions. The altered receptor tyrosine kinase (RTK) pathway is important in UC tumorigenesis. Through data mining of a published transcriptome of UBUC (GSE31684), we identified Discoidin domain receptor 2 (DDR2) as the most significantly upregulated gene in UC progression among the transmembrane receptor protein tyrosine kinase activity (GO:0004714). We then analyzed DDR2 expression and association with clinicopathologic characteristics 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 DDR2 transcript level in 26 UBUCs and 26 UTUCs . Immunohistochemistry evaluated by H-score was used to determine DDR2 protein expression in 340 UTUCs and 295 UBUCs. In this retrospective study, DDR2 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 DDR2 using RNA interference in DDR2-overexpressing UC cells.
Results: An increased DDR2 mRNA level was associated with advanced pT stage in UTUC (P=0.003) and UBUC (P<0.001). High DDR2 expression was significantly associated with higher tumor pT stage, high histological grade, vascular and perineural invasion, and higher mitotic rate. In multivariate Cox regression analyses, adjusted for standard clinicopathologic features, DDR2 overexpression was independently associated with DSS (UTUC hazard ratio [HR]=2.6.37, P = 0.003; UBUC HR=3.488, P=0.001) and with MeFS (UTUC HR=2.797, P<0.001; UBUC HR=2.006, P=0.008). In vitro, knockdown of DDR2 gene resulted in a significant depletion of cellular viability, migratory, and invasive ability in UMUC3 and BFTC909 cells.
Conclusions: DDR2 overexpression is independently associated with tumor progression and dismal survival in UC patients, suggesting it may serve as a novel prognostic marker and therapeutic target.