Abstract
Here, we discovered TGFBI as a new urinary biomarker for muscle invasive and high-grade urothelial carcinoma (UC). After biomarker identification using antibody arrays, results were verified in urine samples from a study population consisting of 303 patients with UC, and 128 urological and 58 population controls. The analyses of possible modifying factors (age, sex, smoking status, urinary leukocytes and erythrocytes, and history of UC) were calculated by multiple logistic regression. Additionally, we performed knockdown experiments with TGFBI siRNA in bladder cancer cells and investigated the effects on proliferation and migration by wound closure assays and BrdU cell cycle analysis. TGFBI concentrations in urine are generally increased in patients with UC when compared to urological and population controls (1321.0 versus 701.3 and 475.6 pg/mg creatinine, respectively). However, significantly increased TGFBI was predominantly found in muscle invasive (14,411.7 pg/mg creatinine), high-grade (8190.7 pg/mg) and de novo UC (1856.7 pg/mg; all p < 0.0001). Knockdown experiments in vitro led to a significant decline of cell proliferation and migration. In summary, our results suggest a critical role of TGFBI in UC tumorigenesis and particularly in high-risk UC patients with poor prognosis and an elevated risk of progression on the molecular level.
Highlights
Urothelial carcinoma (UC) continues to be a predominant cancer worldwide, with an estimated number of 386,000 new cancer cases every year
To verify that Transforming growth factor beta-induced (TGFBI) was predominantly secreted by bladder cancer cells and not surrounding cells, we evaluated its secretion in immortalized normal cells of the bladder (UROtsa), and in addition, different human bladder cancer cell lines isolated from patients with muscle invasive bladder cancer (5637, J82)
platelet-factor 4 (PF4) at first, after screening with the protein array, seemed to represent a promising candidate, the subsequent confirmation by ELISA analyses and the evaluation of a larger sample set showed a much weaker performance compared to TGFBI
Summary
Urothelial carcinoma (UC) continues to be a predominant cancer worldwide, with an estimated number of 386,000 new (de novo) cancer cases every year. When we examined the influence of clinically relevant characteristics, such as stage and grade, on TGFBI levels we were able to confirm significantly higher TGFBI values in high-grade UC (exp(β) = 42.34, 95% CI 7.60–235.94) and in muscle invasive UC patients (exp(β) = 33.84, 95% CI 5.01–228.29) compared to the population controls (Table 2). The results revealed that, to a certain extent, the presence of leukocytes and erythrocytes alone or in combination affected the TGFBI concentration in urine (Supplementary Tables S1 and S2) This relationship was observed in all subgroups; when being positive for both leukocytes and erythrocytes, the median values of TGFBI in urine were ten times higher in high-grade and/or muscle invasive UC patients (21,275 pg/mL) than in controls (2318 pg/mL; Supplementary Table S2)
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