Dataset Information

SPARC stimulates neuronal differentiation of medulloblastoma cells via the Notch1/STAT3 pathway.

ABSTRACT: Secreted protein acidic and rich in cysteine (SPARC) participates in the regulation of morphogenesis and cellular differentiation through its modulation of cell-matrix interactions. We previously reported that SPARC expression significantly impairs medulloblastoma tumor growth in vivo. In this study, we show that adenoviral-mediated overexpression of SPARC cDNA (Ad-DsRed-SP) elevated the expression of the neuronal markers NeuN, nestin, neurofilament, and MAP-2 in medulloblastoma cells and induced neuron-like differentiation. SPARC overexpression decreased STAT3 phosphorylation; constitutive expression of STAT3 reversed SPARC-mediated expression of neuronal markers. We also show that Notch signaling is suppressed in the presence of SPARC, as well as the Notch effector basic helix-loop-helix (bHLH) transcription factor hairy and enhancer of split 1 (HES1). Notch signaling was found to be responsible for the decreased STAT3 phosphorylation in response to SPARC expression. Furthermore, expression of SPARC decreased the production of interleukin 6 (IL-6) and supplemented IL-6-abrogated, SPARC-mediated suppression of Notch signaling and expression of neuronal markers. Immunohistochemical analysis of tumor sections from mice treated with Ad-DsRed-SP showed increased immunoreactivity for the neuronal markers and a decrease in Notch1 expression and phosphorylation of STAT3. Taken together, our results suggest that SPARC induces expression of neuronal markers in medulloblastoma cells through its inhibitory effect on IL-6-regulated suppression of Notch pathway-mediated STAT3 signaling, thus giving further support to the potential use of SPARC as a therapeutic candidate for medulloblastoma treatment. Findings show that SPARC-induced neuronal differentiation can sensitize medulloblastoma cells for therapy.

SUBMITTER: Bhoopathi P

PROVIDER: S-EPMC3138830 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SPARC stimulates neuronal differentiation of medulloblastoma cells via the Notch1/STAT3 pathway.

Bhoopathi Praveen P Chetty Chandramu C Dontula Ranadheer R Gujrati Meena M Dinh Dzung H DH Rao Jasti S JS Lakka Sajani S SS

Cancer research 20110525 14

Secreted protein acidic and rich in cysteine (SPARC) participates in the regulation of morphogenesis and cellular differentiation through its modulation of cell-matrix interactions. We previously reported that SPARC expression significantly impairs medulloblastoma tumor growth in vivo. In this study, we show that adenoviral-mediated overexpression of SPARC cDNA (Ad-DsRed-SP) elevated the expression of the neuronal markers NeuN, nestin, neurofilament, and MAP-2 in medulloblastoma cells and induce ...[more]

PMID: 21613407

Similar Datasets

Project description:BackgroundEndometriosis, characterized by the presence of functional endometrial tissues outside the uterus, is one of the most common gynecological disorders. Endometrial mesenchymal stem cells (MSCs) are crucial for the occurrence and development of endometriosis. Ectopic endometrial MSCs exist in the peritoneal cavity. Thus, the bioactive factors in endometriotic peritoneal fluid may regulate the biological behaviors of endometrial MSCs.MethodsIn this study, after assessing the concentration of Activin A in peritoneal fluid using ELISA, we isolated and cultured endometrial MSCs and investigated whether Activin A stimulated endometrial MSCs to differentiate into myofibroblasts and clarified the underlying mechanisms by quantitative real-time PCR, Western blot analysis, immunofluorescent staining, RNA interference and Chromatin immunoprecipitation. We also employed the inhibitors of Activin A to explore the possibility of suppressing the development of fibrosis in endometriosis using primary endometrial MSCs cultures and a mouse model of endometriosis.ResultsHere, we revealed that Activin A significantly elevated in endometriotic peritoneal fluid and activin receptor-like kinase (ALK4), the specific receptor for Activin A, obviously enhanced in ectopic endometrial MSCs compared with eutopic endometrial MSCs from women with or without endometriosis. Next, we found that Activin A drived myofibroblast differentiation of endometrial MSCs, with extremely enhanced expression of connective tissue growth factor (CTGF). CTGF was shown to be required for Activin A-induced expression of ACTA2, COL1A1 and FN1 in endometrial MSCs. CTGF induction by Activin A in endometrial MSCs involved the activation of Smad2/3, as evidenced by the phosphorylation and nuclear translocation of Smad2/3 as well as the binding of Smad2/3 to CTGF promoter. Furthermore, Smad/CTGF pathway in endometrial MSCs required activation of STAT3 while independent of PI3K, JNK and p-38 pathways. In addition, we also demonstrated that inhibition of Activin A pathway impeded myofibroblast differentiation of endometrial MSCs and ameliorated fibrosis in endometriosis mice.ConclusionsActivin A promotes myofibroblast differentiation of endometrial mesenchymal stem cells via STAT3-dependent Smad/CTGF pathway. The results provided the first evidence that STAT3 acted as a crucial Activin A downstream mediator to regulate CTGF production. Our data may supplement the stem cell theory of endometriosis and provide the experimental basis to treat endometriosis-associated fibrosis by manipulating Activin A signaling.

Dataset Information

SPARC stimulates neuronal differentiation of medulloblastoma cells via the Notch1/STAT3 pathway.

Publications

SPARC stimulates neuronal differentiation of medulloblastoma cells via the Notch1/STAT3 pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets