Loss of SPARC in bladder cancer enhances carcinogenesis and progression
Neveen Said, … , Rolf A. Brekken, Dan Theodorescu
Neveen Said, … , Rolf A. Brekken, Dan Theodorescu
Published January 16, 2013
Citation Information: J Clin Invest. 2013;123(2):751-766. https://doi.org/10.1172/JCI64782.
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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-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.

Authors

Neveen Said, Henry F. Frierson, Marta Sanchez-Carbayo, Rolf A. Brekken, Dan Theodorescu

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Figure 10

Effect of SPARC on UC cell proliferation in in vitro and in vivo tumorigenicity.

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Effect of SPARC on UC cell proliferation in in vitro and in vivo tumorig...
(A) Western blots showing the expression of SPARC protein in 20 μg protein of UMUC3 (top panel), T24, and T24T (bottom panel) human bladder cancer cell lines after overexpression and/or depletion of SPARC. The effect of genetic manipulation of SPARC on UC cell proliferation was determined by CyQuant assay. UMUC3, T24, and T24T transfected with full-length SPARC in pcDNA3.1 (pSP) and pcDNA3.1 empty vector control (VC) or transduced with lentiviral vector laden with short hairpin targeting Sparc gene (shSP) and its irrelevant nontarget control (NTsh). Representative growth curves of cell proliferation measured at 24, 48, and 72 hours performed twice in quadruplicate. *P < 0.05, comparing cells overexpressing SPARC (pSP) with their matching VC; **P < 0.05, comparing cells depleted of SPARC with their matching NTsh, Student’s t test. (B) Western blot of cycle regulatory proteins cyclins A, D, and E and their inhibitors p21 and p27 in 20 μg of the aforementioned cell lines. Equal protein loading was confirmed by reprobing blots with tubulin. (C) Scatter plots representing s.c. tumor take and volume of the UMUC3 T24, and T24T genetically manipulated for SPARC expression after injection in nude mice. *P < 0.05, χ2 test; **P < 0.05, 2-tailed Student’s t test.