Inhibitory Role of the Small Leucine-Rich Proteoglycan Biglycan in Bladder Cancer

Abstract

BackgroundUrothelial bladder cancer is the ninth most common cancer. Despite surgical and chemotherapeutic treatment the prognosis is still poor once bladder cancer progresses to a muscle-invasive state. Discovery of new diagnostic markers and pathophysiologic effectors might help to contribute to novel diagnostic and therapeutic options. The extracellular matrix microenvironment shaped by the extracellular matrix critically affects tumor cell and stroma cell functions. Therefore, aim of the present study was to assess the possible implication of the small leucine-rich proteoglycan biglycan in progression of human urothelial bladder cancer.Methods and ResultsFor this purpose tumor biopsies of 76 bladder cancer patients with different tumor stages (pTa, pT1-T4) were investigated with respect to biglycan expression and correlated with a long-term (10 years) clinical follow-up. Interestingly, higher biglycan mRNA expression was associated with higher tumor stages and muscle invasiveness. In vitro knock-down of endogenous biglycan in human urothelial carcinoma cells (J82 cells) increased proliferation, whereas addition of recombinant biglycan and overexpression of biglycan inhibited tumor cell proliferation. In line with this growth-inhibitory effect of biglycan, transplantation of J82 cells after knock-down of biglycan resulted in significantly increased growth of subcutaneous xenograft tumors in nude mice in vivo. Furthermore, treatment with two anti-proliferative, multi-receptor tyrosine kinase inhibitors—sunitinib and sorafenib—strongly upregulated biglycan expression. Collectively, the experimental data suggest that high biglycan expression is associated with reduced tumor cell proliferation. In accordance, Kaplan-Meier analysis revealed higher 10-year survival in patients with high biglycan mRNA expression in tumor biopsies.ConclusionIn conclusion, the present data suggest that biglycan is an endogenous inhibitor of bladder cancer cell proliferation that is upregulated in response to anti-proliferative tyrosine kinase inhibitors. In addition, high biglycan expression is associated with favorable prognosis.

Biglycan enhances the ability of migration and invasion in endometrial cancer

“…However, the best survival rate was displayed in human bladder cancer with high BGN gene level. The in vivo and in vitro experiment that knockdown BGN enhanced the proliferation ability of bladder cancer cells was agreed with the results, indicating that BGN may be a growth suppressor in human bladder cancer [16]. To our knowledge of inflammation effects on tumorigenesis, it suggests that BGN, similar to decorin, might inhibit tumor growth of established tumors by creating the TLR2/4-mediated proinflammatory environment.…”

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

“…35 In cancer, seemingly contradicting data have revealed that increased BGN expression is linked with poor prognosis, 36 whereas its overexpression was associated with inhibition of cancer cell growth. 37,38 We investigated the loss of BGN in the absence of TAp73 (W1 cells) and revealed that Bgn expression was drastically reduced in TAp73-deficient cells compared with that in 4A cells as well as in Panc1 cells transfected with TAp73 siRNA compared with that in Panc1 cells transfected with siCtr (Figure 4d). This suggests that Bgn, which has seven response elements for p53 family proteins according to the p53FamTaG database, 39 could be a direct transcriptional target of TAp73.…”

Altered expression of small leucine-rich proteoglycans (Decorin, Biglycan and Lumican): Plausible diagnostic marker in urothelial carcinoma of bladder

“…This finding was also supported by showing a significantly higher immunostaining for Biglycan in ESCC. A single study by Niedworok et al 45 in urinary bladder cancer had demonstrated an increase in Biglycan expression at mRNA level as well as at protein level by IHC. Thus, our results on Biglycan expression are also in accordance with the previous studies.…”