title: DPP4/CD26 overexpression in urothelial carcinoma confers an independent prognostic impact and correlates with intrinsic biological aggressiveness.
abstract: Urothelial carcinoma (UC) is common cancer worldwide. The molecular aberrations regarding tumor progression remain unclear. Pericellular proteolysis is crucial in tumorigenesis, but its significance is unexplored in UC. By data mining the datasets in Gene Expression Omnibus, specifically focus on the proteolysis pathway, and followed by a preliminary validation in a pilot batch of tumor samples, we identified that the upregulation of dipeptidyl peptidase 4 (DPP4) was most significantly associated with clinical aggressiveness of UCs. Quantitative RT-PCR confirmed upregulation of DPP4 mRNA in advanced stage UCs. The clinical significance of DPP4 expression was validated in our large cohort consists of 635 UCs from upper urinary tract and urinary bladder. Univariate and multivariate analyses show that DPP4 is an independent prognosticatory biomarker for disease-specific survival and metastasis-free survival. Comparing the DPP4 expression level of three urothelial cell lines with normal urothelial cells, J82 and RTCC-1 showed a significantly increased in transcript and protein expression. DPP4 knockdown as conducted by using short-hairpin RNA resulted in a significantly decreased cell viability, proliferation, migration, and invasion in J82 and RTCC-1 cells. These findings implicate that DPP4 plays a role in the aggressiveness of UCs, and can serve as a novel prognostic marker and therapeutic target.
authors.affiliation: Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Peir-In
authors.initials: PI
authors.lastname: Liang
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung, Medical University, Kaohsiung, Taiwan.
authors.forename: Bi-Wen
authors.initials: BW
authors.lastname: Yeh
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung, Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Li
authors.affiliation: Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.|Institute of Biomedical Science, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Ti-Chun
authors.initials: TC
authors.lastname: Chan
authors.affiliation: Department of Pathology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan.|School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.
authors.forename: I-Wei
authors.initials: IW
authors.lastname: Chang
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung, Medical University, Kaohsiung, Taiwan.
authors.forename: Chun-Nung
authors.initials: CN
authors.lastname: Huang
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung, Medical University, Kaohsiung, Taiwan.|Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
authors.forename: Ching-Chia
authors.initials: CC
authors.lastname: Li
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung, Medical University, Kaohsiung, Taiwan.
authors.forename: Hung-Lung
authors.initials: HL
authors.lastname: Ke
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung, Medical University, Kaohsiung, Taiwan.|Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
authors.forename: Hsin-Chih
authors.initials: HC
authors.lastname: Yeh
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung, Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Wen-Jeng
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.|Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan.|Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014523:Urethral Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D014571:Urologic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: DPP4; overexpression; proteolysis; urothelial carcinoma