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In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type

Abstract

Altered expression of CCN3 has been observed in a variety of musculoskeletal tumours, including Ewing's sarcoma (ES). Despite its widespread distribution, very little is known about its biological functions and molecular mechanisms of action. We transfected CCN3 gene into a CCN3-negative ES cell line and analysed the in vitro and in vivo behaviours of stably transfected clones. Forced expression of CCN3 significantly reduced cell proliferation in vitro, growth in anchorage-independent conditions and tumorigenicity in nude mice. Despite the antiproliferative effect, CCN3-transfected ES cells displayed increased migration and invasion of Matrigel. The decreased expression of α2β1 integrin receptor and the increased amount of cell surface-associated matrix metalloproteinase (MMP)-9 following the expression of CCN3 may be the basis for the increased migratory abilities of transfected cells. Cells lacking α2β1 are less facilitated to have stable anchorage since the predominant collagen extracted from ES tissue is indeed type I collagen and proMMP-9 was recently found to provide a cellular switch between stationary and migratory ES cell phase. Our findings are in line with those recently obtained in glioblastoma. However, the underlying molecular mechanisms appear to be different, further highlighting the importance of the cellular context in the regulation of function of CCN proteins.

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Abbreviations

NOV :

nephroblastoma overexpressed gene

Cyr61:

cystein-rich protein 61

CTGF:

connective tissue growth factor

PDGF:

platelet-derived growth factor

ECM:

extracellular matrix

ES:

Ewing's sarcoma

MMP:

metalloprotease

PDGFR:

platelet-derived growth factor receptor

MAPK:

mitogen-activated protein kinase

IGF:

insulin-like growth factor

IGF-IR:

insulin-like growth factor receptor I

MAb:

monoclonal antibody

IMDM:

Iscove's modified Dulbecco's medium

FBS:

fetal bovine serum

RT–PCR:

reverse transcription polymerase chain reaction

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Acknowledgements

This work was supported by grants from the Italian Association for Cancer Research and the Italian Ministry of Health. Experiments performed in the laboratory of B Perbal were funded by Association pour la Recherche contre le Cancer (ARC), Ligue Nationale contre le Cancer (Comités du Cher et de l'Indre) and Ministère de l'Education Nationale et de la Recherche. SB performed constructions of the vectors in the laboratory of B Perbal when she was supported by a UICC International Cancer Technology Transfer Fellowship (ICRETT). We thank Professor Bernard Roizman (University of Chicago) who provided facilities and support B Perbal for the initial construction of pCMV derivatives and Professor Stanimir Kyurkchiev for CCN3 purification.

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Benini, S., Perbal, B., Zambelli, D. et al. In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type. Oncogene 24, 4349–4361 (2005). https://doi.org/10.1038/sj.onc.1208620

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