DPP4過度表現對於尿路上皮癌病人預後之影響
李威明1,2,3、連培因4、吳文正1,3,5、李經家1,3、柯宏龍1,3、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 impact of DPP4 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 carcinomas (UC) of urinary bladder (UB) and upper urinary tract (UT) are heterogeneous diseases with high morbidity and mortality The molecular aberrations regarding tumor progression remain unclear. Pericellular proteolysis is crucial in tumorigenesis, but its significance is unexplored in UC. Through data mining of a published transcriptome of UBUC (GSE32894), we identified dipeptidyl peptidase 4 (DPP4) as the most significantly upregulated gene in UC progression among the proteolysis pathway. We then analyzed DPP4 expression and association with clinicopathologic factors and survival in our well-characterized cohort of UCs.
Materials and Methods: We performed laser capture microdissection coupled with real-time reverse transcriptase-polymerase chain reaction assay to determine the DPP4 transcript level in 20 UBUCs. Immunohistochemistry evaluated by H-score was used to determine DPP4 protein expression in 340 UTUCs and 295 UBUCs. In this retrospective study, DPP4 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 DPP4 using RNA interference in DPP4-overexpressing UC cells.
Results: An increased DPP4 mRNA level was associated with higher pT stage in UBUC (P<0.001). High DPP4 expression was significantly associated with higher tumor pT stage, nodal metastasis, high histological grade, vascular and perineural invasion, and frequent mitosis. In multivariate Cox regression analyses, adjusted for standard clinicopathologic features, DPP4 overexpression was independently associated with DSS (UTUC hazard ratio [HR]=2.383, P = 0.028; UBUC HR=3.562, P<0.001) and with MeFS (UTUC HR=2.048, P=0.031; UBUC HR=3.530, P<0.001).In vitro, knockdown of DPP4 gene significantly suppressed cell viability, proliferation, migration, and invasion in J82 and RTCC-1 cells.
Conclusions: DPP4 overexpression is associated with aggressive tumor phenotype and unfavorable clinical outcome in UCs, suggesting it may serve as a novel prognostic marker and therapeutic target.