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.

Systemic DPP4 activity is reduced during primary HIV‐1 infection and is associated with intestinal RORC+CD4+ cell levels: a surrogate marker candidate of HIV‐induced intestinal damage

“…sDPP4 was quantified before infection (N = 87), in primary HIV infection (PHI, N = 36), at three months post‐seroconversion (M3, N = 126) and six months post‐seroconversion (M6, N = 104). In most studies, the levels of sDDP4 are measured at the level of its enzymatic activity and absolute concentrations are more rarely presented . We measured both and as in previous studies , found a strong correlation between the concentration and enzymatic activity of sDDP4 ( R = 0.72, p < 0.0001 and Figure A).…”

“…multiple sclerosis, rheumatoid arthritis) and cancer (i.e. B‐cell leukaemia, hepatocellular carcinoma, bladder cancer) . In addition, DPP4 inhibitors are a widely used therapy for type II diabetes .…”

Dipeptidyl peptidase 4 inhibitors as novel agents in improving survival in diabetic patients with colorectal cancer and lung cancer: A Surveillance Epidemiology and Endpoint Research Medicare study

“…It plays an important role in tumor biology by acting as a tumor suppressor or activator depending upon the level of expression and its interaction with the microenvironment and selected chemokines . In animal models, DPP4/CD26 expression has been shown to be of prognostic value and is a potential therapeutic target in various malignancies . Of note is that the first phase I clinical trial involving CD26‐expressing cancers with an anti‐CD26 monoclonal antibody was recently completed and reported prolonged disease stabilization in patients with mesothelioma with good drug tolerance …”

“…[1][2][3] In animal models, DPP4/CD26 expression has been shown to be of prognostic value and is a potential therapeutic target in various malignancies. [4][5][6][7] Of note is that the first phase I clinical trial involving CD26-expressing cancers with an anti-CD26 monoclonal antibody was recently completed and reported prolonged disease stabilization in patients with mesothelioma with good drug tolerance. 8 Barreira da Silva et al 9 showed that in mice models with melanoma, DPP4 inhibition preserved the active form of chemokine CXCL10 which recruits T cells in tumor parenchyma.…”

Pioglitazone-mediated reversal of elevated glucose metabolism in the airway epithelium of mouse lung adenocarcinomas

“…UDP-glucose pyrophosphorylase 2 (UDP-UGP2) encodes the enzyme important for glucose synthesis, and its expression has been found to be associated with poor outcome of a number of cancers (33,34). Dipeptidyl peptidase 4 (DPP4) functions as an ectopeptidase that can inactivate incretins, catalyze the cleavage of chemokines, promote cell migration, and activate lymphocytes; its expression is linked to the carcinogenesis of many malignant tumors (35). Calcium channel β 3 (CACNB3) was one member gene of a 4-gene prognostic model exhibiting potential clinical utility for risk stratification of stage I to stage III NSCLC patients (36).…”