DPP4/CD26 overexpression in urothelial carcinoma confers an independent prognostic impact and correlates with intrinsic biological aggressiveness.

Peir-In Liang,Chun-Nung Huang,Hsin-Chih Yeh,Wen-Jeng Wu,Ti-Chun Chan,Hung-Lung Ke,Ching-Chia Li,Wei-Ming Li,Bi-Wen Yeh,I-Wei Chang,Chien-Feng Li

doi:10.18632/oncotarget.13820

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.

Highlights

Urothelial carcinoma (UC) is common cancer worldwide that arises from both the upper urinary tract (UUT, renal pelvis, and ureter) and lower urinary tract (LUT, urinary bladder, and urethra). [1] Generally, the incidence of UC of the urinary bladder (UBUC) is more frequent than UC of the upper urinary tract (UTUC); the ratio of the incidence of urothelial carcinoma in the renal pelvis, ureter, and urinary bladder is approximately 3:1:51. [2] The etiology of UC, regardless of location, includes smoking cigarettes and exposure to aromatic amines containing chemicals
By data mining the datasets in Gene Expression Omnibus, 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
By mining the datasets obtained from the Gene Expression Omnibus (GEO, NCBI, Bethesda, MD, USA) and focused on the proteolysis pathway, we discovered that the transcription of dipeptidyl peptidase 4 (DPP4) was significantly upregulated in advanced-stage human urothelial carcinomas

Summary

Introduction

Urothelial carcinoma (UC) is common cancer worldwide that arises from both the upper urinary tract (UUT, renal pelvis, and ureter) and lower urinary tract (LUT, urinary bladder, and urethra). [1] Generally, the incidence of UC of the urinary bladder (UBUC) is more frequent than UC of the upper urinary tract (UTUC); the ratio of the incidence of urothelial carcinoma in the renal pelvis, ureter, and urinary bladder is approximately 3:1:51. [2] The etiology of UC, regardless of location, includes smoking cigarettes and exposure to aromatic amines containing chemicals. Urothelial carcinoma (UC) is common cancer worldwide that arises from both the upper urinary tract (UUT, renal pelvis, and ureter) and lower urinary tract (LUT, urinary bladder, and urethra). [1] Generally, the incidence of UC of the urinary bladder (UBUC) is more frequent than UC of the upper urinary tract (UTUC); the ratio of the incidence of urothelial carcinoma in the renal pelvis, ureter, and urinary bladder is approximately 3:1:51. [3] the disease behavior of stage-adjusted UTUC and UBUC is identical, and the gene expression profiles of UCs from both locations are very similar. [3, 4] This may indicate that tumorigenesis of UC arising at any site in the urinary tract shares a common pathway. The increase of proteases production has been reported in various cancers and is often associated with poor outcome [7]

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Conclusion