GFBP5 overexpression as a poor prognostic factor in patients with urothelial carcinomas of upper urinary tracts and urinary bladder

[[abstract]]Background: Urothelial carcinoma (UC) is a prevalent cancer worldwide, especially in developed country. Although urinary bladder urothelial carcinoma (UBUC) is more common than upper urinary tract urothelial carcinoma (UTUC), tumorigenesis of urothelial carcinoma arising from these two areas may share a similar pathway. Dysregulation of cell growth is critical for tumorigenesis but has not been assessed systemically in UC. Data mining of the published UBUC dataset (GSE31684) identified insulin-like growth factor binding protein 5 (IGFBP5) as the most significantly upregulated genes that associated with regulation of cell growth. Besides, IGFBP5 transcript expression level also significantly predicted worse outcome. We therefore analyze IGFBP5 expression and its associations with clincopathological factors and survivals in our well-characterized cohort of UC.Design: IGFBP5 immunostain was performed on 340 cases of upper urinary tract urothelial carcinoma (UTUC) and 295 cases of UBUC. The result of IGFBP5 expression was then correlated with various clincopathological factors disease-specific survival (DSS), and metastasis-free survival (MeFS). Western blot analysis was used to evaluate IGFBP5 protein expression in human urothelial cancer cell lines.Results: In both group of tumors, IGFBP5 overexpression significantly associated with advanced pT stage (both p<0.001), high histological grade (UTUC, p<0.001; UBUC, p=0.035), lymph node metastasis (UTUC, p=0.006; UBUC, p=0.004), vascular invasion (UTUC, p<0.001; UBUC, p=0.003), perineurial invasion (UTUC, p=0.034; UBUC, p=0.021) and frequent mitosis (UTUC, p<0.001; UBUC, p=0.023). IGFBP5 overexpression also independently predicted poor DSS (UTUC, p < 0.0001; UBUC, p = 0.0001) and MeFS (both p < 0.0001) in both groups of patients. IGFBP5 protein was abundant in urothelial cancer cell lines but barely detected in benign urothelial cells.Conclusions: IGFBP5 overexpression is associated with advanced tumor stage and conferred poorer clinical outcome. Our study suggested that IGFBP5 plays an important role in tumor progression in UC, justifying the potentiality of IGFBP5 as a prognostic biomarker and a novel therapeutic target of UC