Abstract
Hyaluronan (HA) is a carbohydrate of the extracellular matrix with tumor promoting effects in a variety of cancers. The present study addressed the role of HA matrix for progression and prognosis of human bladder cancer by studying the expression and function of HA-related genes.MethodsTissue samples of 120 patients with different stages of transitional cell bladder cancer, who underwent surgical treatment for bladder cancer at the University Hospital of Essen were analysed. mRNA-expression levels of HA synthases (HAS1-3) and HA-receptors (RHAMM and CD44) were evaluated by real time RT-PCR in comparison to healthy bladder tissue as control. In uni- and multivariate cox proportional hazard survival regression analysis, the impact of the gene expression levels on survival was assessed. In vitro knock-down of RHAMM, CD44 and HAS isoenzymes was achieved by siRNA and lentiviral shRNA in J82 bladder cancer cells. Transfected cells were analysed in vitro with regard to proliferation, cell cycle and apoptosis. J82 cells after knock-down of RHAMM were xenografted into male nu/nu athymic mice to monitor tumor progression in vivo.ResultsIn invasive tumor stages RHAMM-, HAS1 and HAS2 mRNA-expression levels were elevated whereas HAS3v1 was reduced as compared to non-invasive tumors. Subsequently, Kaplan-Meier analysis revealed reduced bladder cancer specific survival in patients with high RHAMM mRNA and low HAS3v1 expression. Elevated RHAMM in invasive tumors was confirmed by RHAMM immunohistochemistry. Furthermore, multivariate analysis revealed that only RHAMM expression was associated with poor prognosis independent from other survival factors (HR=2.389, 95% CI 1.227-4.651, p=0.01). Lentiviral RHAMM knock-down revealed reduced J82 cell proliferation in vitro and reduced xenograft tumor growth in vivo.ConclusionThe data suggest that RHAMM plays a crucial role in mediating progression of muscle-invasive bladder cancer and recommends RHAMM for further evaluation as a prognostic marker or therapeutic target in bladder cancer therapy.
Highlights
Transitional cell carcinoma (TCC) of the bladder is the ninth most common malignant disease with a global 5-year prevalence of 860,299 males and 249,966 females [1]
While patients with genetically stable nonmuscle invasive low grade tumors show an excellent 5 year survival rate of 96%, patients with deep muscle infiltrating high grade tumors have the worst prognosis with a 5 year survival rate of about 20% [2,3]
Lymph node positivity was present in 23/120 patients. 74 patients suffered from primary BC while 46 patients experienced a recurrent disease. 55 patients were treated by transurethral resection of the TCC, in 65 cases radical cystectomy was performed
Summary
Transitional cell carcinoma (TCC) of the bladder is the ninth most common malignant disease with a global 5-year prevalence of 860,299 males and 249,966 females [1]. In nonmuscle-invasive tumors (Ta) progression to muscle-invasive disease (T2-T4) is rare and occurs in 3 to 5% of all cases [2]. Nonmuscle invasive low grade tumors transurethral resection (TUR) is the local, bladder preserving, therapy of choice. Muscle infiltrating transitional cell carcinomas of the bladder represent a heterogenous group of tumors with regard to clinical outcome. In patients with pT3/4 tumors about 50% are at risk of developing metastases despite of extended surgery. It is of great importance to elucidate the pathophysiology of BC and to develop more precise diagnostic markers for progression of this subset of muscle-invasive carcinomas that confer high risk of cancer specific mortality
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