Interleukin-6 (IL-6) is a multifunctional cytokine that orchestrates the immune response to a wide variety of pathophysiologic challenges but also contributes to tissue homeostasis. Furthermore, IL-6 is elevated in patients with acute myocardial infarction. Hyaluronan (HA) is an extracellular carbohydrate that has been implicated in wound healing and accumulates after acute myocardial infarction (AMI). Aim of this study was to investigate the involvement of IL-6 in the regulation of the HA-matrix in the early phase of infarct healing. In the present study, we show by the use of a blocking anti-IL-6 antibody, that endogenous IL-6 rapidly but transiently increased HA-synthase (HAS) 1 and 2 expression resulting in the formation of a HA-rich matrix acutely after AMI in mice. In vitro, IL-6 induced HAS1 and 2 via STAT3 phosphorylation in cardiac fibroblasts (CF) and supported a myofibroblastic phenotype in a HA-dependent manner. Furthermore, CCL5 and MCP1 expression were dependent on IL-6, HA-synthesis and the HA-receptor CD44 as shown in cultured CF derived from CD44 knockout mice. In vivo after AMI, blocking IL-6 decreased HA-matrix formation in the peri-infarct region and alpha-smooth muscle actin-positive myofibroblasts. Blocking IL-6 also reduced neutrophil infiltration in infarcted left ventricles. Moreover, treatment with the blocking IL-6 antibody reduced cardiac ejection fraction and increased infarct size 3 weeks after AMI. These findings support a functionally important role for IL-6 in CF by transiently inducing a HA-rich matrix that in turn promotes a myofibroblastic phenotype and inflammatory responses, and ultimately establishes a cardioprotective program after AMI.
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.
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.
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