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Background: Through data mining from a published transcriptomic database of urinary bladder urothelial carcinomas (GSE32894), MMP11 was identified as the most significant gene showing stepwise upregulation among those associated with the regulation of metalloendopeptidase activity. We therefore analysed MMP11 protein expression and its association with clinicopathological factors and survival in our well-characterised cohort of urothelial cancers. Methods: Immunohistochemistry evaluated by using H-score was used to determine MMP11 protein expression in 295 urothelial carcinomas of the urinary bladder and 340 urothelial carcinomas of the upper urinary tract, respectively. The medical records of these patients were reviewed retrospectively. The MMP11 expression status was further correlated with clinicopathological features as well as disease-specific survival (DSS) and metastasis-free survival (MeFS). Univariate and multivariate statistical analyses were performed to evaluate the prognostic predictors. Findings: MMP11 protein overexpression was significantly associated with advanced pT status (upper urinary tract, p< 0.001; urinary bladder, p<0.001), nodal metastasis (upper urinary tract, p<0.001; urinary bladder, p=0.012), vascular invasion (upper urinary tract, p<0.001; urinary bladder, p<0.001), and perineural invasion (upper urinary tract, p=0.002; urinary bladder, p=0.006) in both groups of urothelial carcinomas. MMP11 overexpression not only predicted worse DSS (upper urinary tract, p<0.0001; urinary bladder, p<0.0001) and MeFS (upper urinary tract, p<0.0001; urinary bladder, p<0.0001) at univariate analysis, but also inferior DSS (upper urinary tract, p=0.005; urinary bladder, p=0.010) and MeFS (upper urinary tract, p=0.018; urinary bladder, p=0.026) in multivariate analysis. Interpretation: MMP11 overexpression is associated with more aggressive tumour phenotype and poor prognosis for patients with urothelial carcinomas of the upper urinary tract and urinary bladder, suggesting it may serve as a potential prognostic and a novel therapeutic target of urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Background: Dipeptidyl peptidase-4 (DPP4), also known as CD26, is an enzyme that cleaves a diversity of protein that contains proline or analine, including chemokines, growth factors, and neuropeptide. Different DPP4 expression status has been observed in malignant tumours, including colon, renal, and ovarian carcinoma. Data mining of the published dataset (GSE31684) identified that DPP4 is significantly upregulated in urothelial carcinoma of the urinary bladder. We therefore analysed the association of DPP4 expression and outcome in our well-characterised cohort of urothelial carcinoma. Methods: Laser capture microdissection coupled with real-time qRT-PCR was used to evaluate DPP4 transcript level in 20 urothelial carcinomas of the urinary bladder. DPP4 immunostaining was done on 340 cases of urothelial carcinoma of the upper urinary tract and 295 cases of urothelial carcinoma of the urinary bladder. The expression status of DPP4 was then correlated with various clincopathological factors, disease-specific survival (DSS), and metastasis-free survival (MeFS). Findings: DPP4 mRNA expression was significantly increased in urothelial carcinomas with higher pT status (p<0.001). In both groups of urothelial carcinomas, increment of DPP4 immunoexpression was significantly associated with advanced pT stage (both p<0.001), high histological grade (urothelial carcinoma of the upper urinary tract, p=0.019), lymph node metastasis (urothelial carcinoma of the upper urinary tract, p<0.001; urothelial carcinoma of the urinary bladder, p=0.033), vascular invasion (both p<0.001), perineurial invasion (urothelial carcinoma of the urinary bladder, p=0.021) and frequent mitosis (urothelial carcinoma of the upper urinary tract, p=0.003). DPP4 overexpression independently predicted poor DSS (urothelial carcinoma of the upper urinary tract, p=0.028; urothelial carcinoma of the urinary bladder, p<0.0001) and MeFS (urothelial carcinoma of the upper urinary tract, p=0.031; urothelial carcinoma of the urinary bladder, p<0.0001) in both groups of patients. Interpretation: Our study shows that overexpression of DPP4 is significantly associated with aggressive tumour behaviour and poor outcome. DPP4 may have an important role in tumorigenesis of urothelial carcinoma. [ABSTRACT FROM AUTHOR]