title: HER-2/neu-mediated down-regulation of biglycan associated with altered growth properties.
abstract: The extracellular matrix protein biglycan (Bgn) is a leucine-rich proteoglycan that is involved in the matrix assembly, cellular migration and adhesion, cell growth, and apoptosis. Although a distinct expression of Bgn was found in a number of human tumors, the role of this protein in the initiation and/or maintenance of neoplastic transformation has not been studied in detail. Using an in vitro model of oncogenic transformation, a down-regulation of Bgn expression as well as an altered secretion of different Bgn isoforms was found both in murine and human HER-2/neu oncogene-transformed cells when compared with HER-2/neu(-) cells. This was associated with a reduced growth, wound closure, and migration capacity. Vice versa, silencing of Bgn in HER-2/neu(-) fibroblasts increased the growth rate and migration capacity of these cells. Bgn expression was neither modulated in HER-2/neu(+) cells by transforming growth factor-β(1) nor by inhibition of the phosphoinositol 3-kinase and MAP kinase pathways. In contrast, inhibition of the protein kinase C (PKC) pathway led to the reconstitution of Bgn expression. In particular, the PKC target protein cAMP response element binding protein (CREB) is a major regulator of Bgn expression as the silencing of CREB by RNA interference was accompanied by ∼5000-fold increase in Bgn-mRNA expression in HER-2/neu(+) cells. Thus, Bgn inhibits the major properties of HER-2/neu-transformed cells, which is inversely modulated by the PKC signaling cascade.
authors.affiliation: Martin Luther University Halle-Wittenberg, Institute of Medical Immunology, 06112 Halle (Saale), Germany.
authors.forename: Christian V
authors.initials: CV
authors.lastname: Recktenwald
authors.forename: Sandra
authors.initials: S
authors.lastname: Leisz
authors.forename: André
authors.initials: A
authors.lastname: Steven
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.forename: Anja
authors.initials: A
authors.lastname: Müller
authors.forename: Jens
authors.initials: J
authors.lastname: Wulfänger
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
mesh_terms: D000818:Animals; D058578:Biglycan / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D058578:Biglycan; D018719:Erb-b2 Receptor Tyrosine Kinases; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1