Loss of SPARC in bladder cancer enhances carcinogenesis and progression
ABSTRACT Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumor- and stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.
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ABSTRACT: Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behaviour in individual patients. In the present study we analysed combined genome wide DNA methylation and gene expression data of patients treated in the MRC Myeloma IX trial. We used this data to identify epigenetically repressed tumour suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumour modulating genes GPX3, RBP1, SPARC and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, ISS score and adverse cytogenetics. The four differentially methylated and expressed genes are known to mediate important tumour suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signalling (RBP1) and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterisation of myeloma, which is prerequisite for an individualised treatment approach.Blood 05/2013; 122(2). DOI:10.1182/blood-2013-03-487884 · 10.43 Impact Factor
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ABSTRACT: The extracellular matrix undergoes extensive remodeling during hepatocellular carcinoma and functions as a critical component of the tumor microenvironment by providing a substratum for cell adhesion and serving as a reservoir for a variety of cytokines and growth factors. Despite the clinical correlation between ECM deposition and hepatocellular carcinoma progression, it remains unclear how global extracellular matrix gene expression is altered in hepatocellular carcinoma and the molecular pathways that govern this change. Herein, a comprehensive analysis of the extracellular matrix transcriptome using an RNA-sequencing dataset provided by The Cancer Genome Atlas consortium was conducted and indicates substantial differential gene expression of key extracellular matrix collagens, glycoproteins, and proteoglycans in hepatocellular carcinoma. This analysis also reveals alternative expression of extracellular matrix gene transcript variants that could impact biological activity and serves as a framework for exploring the dynamic nature of the extracellular matrix transcriptome in cancer and identifying candidate genes for future exploration.Matrix biology: journal of the International Society for Matrix Biology 05/2013; DOI:10.1016/j.matbio.2013.05.003 · 3.65 Impact Factor