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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-?B 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.

SUBMITTER: Said N

PROVIDER: S-EPMC3561835 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Loss of SPARC in bladder cancer enhances carcinogenesis and progression.

Said Neveen N Frierson Henry F HF Sanchez-Carbayo Marta M Brekken Rolf A RA Theodorescu Dan D

The Journal of clinical investigation 20130116 2

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 ...[more]

PMID: 23321672

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Project description:BackgroundInvasion and metastasis are the main causes of unfavourable prognosis in patients diagnosed with bladder cancer. The efficacy of immunotherapy in bladder cancer remains suboptimal due to the presence of an immunosuppressive microenvironment. The novel protein family with sequence similarity 171B (FAM171B) has been identified, but its precise role and mechanism in bladder cancer remain unclear.MethodsIn this study, we conducted an analysis to investigate the associations between FAM171B expression and the prognosis and clinicopathological stage of bladder cancer. To this end, we utilized RNA sequencing data from the TCGA and GEO databases, as well as tumor tissue specimens obtained from our clinical centre. RNA sequencing analysis allowed us to examine the biological function of FAM171B at the transcriptional level in bladder cancer cells. Additionally, we used immunoprecipitation and mass spectrometry to identify the protein that interacts with FAM171B in bladder cancer cells. The effects of FAM171B on modulating tumor-associated macrophages (TAMs) and vimentin-mediated tumor progression, as well as the underlying mechanisms, were clarified by phalloidin staining, immunofluorescence staining, ELISA, RNA immunoprecipitation, flow cytometry and a bladder cancer graft model.ResultsFAM171B expression exhibits strong positive correlation with poor survival outcomes and advanced clinicopathological stages in patients with bladder cancer. FAM171B significantly promoted bladder cancer growth and metastasis, accompanied by TAM accumulation in the microenvironment, in vivo and in vitro. Through studies of the molecular mechanism, we found that FAM171B contributes to tumor progression by stabilizing vimentin in the cytoplasm. Additionally, our research revealed that FAM171B enhances the splicing of CCL2 mRNA by interacting with heterogeneous nuclear ribonucleoprotein U (HNRNPU), ultimately leading to increased recruitment and M2 polarization of TAMs.ConclusionsIn this study, we identified FAM171B as a potent factor that promotes the progression of bladder cancer. These findings establish a solid theoretical foundation for considering FAM171B as a potential diagnostic and therapeutic biomarker for bladder cancer.

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Loss of SPARC in bladder cancer enhances carcinogenesis and progression.

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Loss of SPARC in bladder cancer enhances carcinogenesis and progression.

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