Tumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7- and ERK-dependent manner

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dc.contributor.authorvan Rooyen, Beverleyen_ZA
dc.contributor.authorSchafer, Georgiaen_ZA
dc.contributor.authorLeaner, Virnaen_ZA
dc.contributor.authorParker, Men_ZA
dc.date.accessioned2015-11-27T09:32:18Z
dc.date.available2015-11-27T09:32:18Z
dc.date.issued2013en_ZA
dc.description.abstractBACKGROUND: Recent studies have revealed that interactions between tumour cells and the surrounding stroma play an important role in facilitating tumour growth and invasion. Stromal fibroblasts produce most of the extracellular matrix components found in the stroma. The aim of this study was to investigate mechanisms involved in tumour cell-mediated regulation of extracellular matrix and adhesion molecules in co-cultured fibroblasts. To this end, microarray analysis was performed on CCD-1068SK human fibroblast cells after direct co-culture with MDA-MB-231 human breast tumour cells. RESULTS: We found that the expression of both connective tissue growth factor (CTGF/CCN2) and type I collagen was negatively regulated in CCD-1068SK fibroblast cells under direct co-culture conditions. Further analysis revealed that Smad7, a known negative regulator of the Smad signalling pathway involved in CCN2 promoter regulation, was increased in directly co-cultured fibroblasts. Inhibition of Smad7 expression in CCD-1068SK fibroblasts resulted in increased CCN2 expression, while Smad7 overexpression had the opposite effect. Silencing CCN2 gene expression in fibroblasts led, in turn, to a decrease in type I collagen mRNA and protein levels. ERK signalling was also shown to be impaired in CCD-1068SK fibroblasts after direct co-culture with MDA-MB-231 tumour cells, with Smad7 overexpression in fibroblasts leading to a similar decrease in ERK activity. These effects were not, however, seen in fibroblasts that were indirectly co-cultured with tumour cells. CONCLUSION: We therefore conclude that breast cancer cells require close contact with fibroblasts in order to upregulate Smad7 which, in turn, leads to decreased ERK signalling resulting in diminished expression of the stromal proteins CCN2 and type I collagen.en_ZA
dc.identifier.apacitationvan Rooyen, B., Schafer, G., Leaner, V., & Parker, M. (2013). Tumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7- and ERK-dependent manner. <i>Cell Communication and Signaling</i>, http://hdl.handle.net/11427/15390en_ZA
dc.identifier.chicagocitationvan Rooyen, Beverley, Georgia Schafer, Virna Leaner, and M Parker "Tumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7- and ERK-dependent manner." <i>Cell Communication and Signaling</i> (2013) http://hdl.handle.net/11427/15390en_ZA
dc.identifier.citationVan Rooyen, B. A., Schäfer, G., Leaner, V. D., & Parker, M. I. (2013). Tumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7-and ERK-dependent manner. Cell Communication and Signaling, 11(1), 75.en_ZA
dc.identifier.ris TY - Journal Article AU - van Rooyen, Beverley AU - Schafer, Georgia AU - Leaner, Virna AU - Parker, M AB - BACKGROUND: Recent studies have revealed that interactions between tumour cells and the surrounding stroma play an important role in facilitating tumour growth and invasion. Stromal fibroblasts produce most of the extracellular matrix components found in the stroma. The aim of this study was to investigate mechanisms involved in tumour cell-mediated regulation of extracellular matrix and adhesion molecules in co-cultured fibroblasts. To this end, microarray analysis was performed on CCD-1068SK human fibroblast cells after direct co-culture with MDA-MB-231 human breast tumour cells. RESULTS: We found that the expression of both connective tissue growth factor (CTGF/CCN2) and type I collagen was negatively regulated in CCD-1068SK fibroblast cells under direct co-culture conditions. Further analysis revealed that Smad7, a known negative regulator of the Smad signalling pathway involved in CCN2 promoter regulation, was increased in directly co-cultured fibroblasts. Inhibition of Smad7 expression in CCD-1068SK fibroblasts resulted in increased CCN2 expression, while Smad7 overexpression had the opposite effect. Silencing CCN2 gene expression in fibroblasts led, in turn, to a decrease in type I collagen mRNA and protein levels. ERK signalling was also shown to be impaired in CCD-1068SK fibroblasts after direct co-culture with MDA-MB-231 tumour cells, with Smad7 overexpression in fibroblasts leading to a similar decrease in ERK activity. These effects were not, however, seen in fibroblasts that were indirectly co-cultured with tumour cells. CONCLUSION: We therefore conclude that breast cancer cells require close contact with fibroblasts in order to upregulate Smad7 which, in turn, leads to decreased ERK signalling resulting in diminished expression of the stromal proteins CCN2 and type I collagen. DA - 2013 DB - OpenUCT DO - 10.1186/1478-811X-11-75 DP - University of Cape Town J1 - Cell Communication and Signaling LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Tumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7- and ERK-dependent manner TI - Tumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7- and ERK-dependent manner UR - http://hdl.handle.net/11427/15390 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15390
dc.identifier.urihttp://dx.doi.org/10.1186/1478-811X-11-75
dc.identifier.vancouvercitationvan Rooyen B, Schafer G, Leaner V, Parker M. Tumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7- and ERK-dependent manner. Cell Communication and Signaling. 2013; http://hdl.handle.net/11427/15390.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentDivision of Medical Biochemistryen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holder2013 van Rooyen et al.; licensee BioMed Central Ltd.en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_ZA
dc.sourceCell Communication and Signalingen_ZA
dc.source.urihttp://www.biosignaling.com/en_ZA
dc.subject.otherFeedback regulationen_ZA
dc.subject.otherCCN2en_ZA
dc.subject.otherType 1 collagenen_ZA
dc.subject.otherSignal transductionen_ZA
dc.subject.otherHost-tumour cell interactionen_ZA
dc.subject.otherBreast canceren_ZA
dc.titleTumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7- and ERK-dependent manneren_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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