Characterization of tenascin-C-induced signaling in tumorigenesis

摘要: During cancer progression, the extracellular matrix (ECM) is extensively remodeled. The ECM molecule tenascin-C an adhesion-modulating molecule, which highly expressed in tumor stroma. Tenascin-C was shown to disrupt interaction of cells with fibronectin, adhesive through inhibition syndecan-4, co-receptor fibronectin binding integrin α5β1. Cells on a mixed substratum and failed form cell adhesion structures actin stress fibers thus remained rounded. Focal kinase (FAK) (Huang et al., 2001; Orend, 2003) small GTPase RhoA (Wenk 2000), two molecules important role formation focal adhesions fibers, were downregulated presence tenascin-C. Furthermore, actin-binding filament-stabilizing tropomyosin-1 (TM1) identified by Ruiz (2004) be its downregulation contributed lack fiber fibronectin/tenascin-C substratum. Here, we investigated signaling events, that lead rounding In particular, wanted understand how prevents affects expression function three downstream targets FAK, TM1. First, whether syndecan-4 linked reduced TM1 FAK. By activating observed indeed this case. Thus, repression could explain fibronectin/tenascin-C. Whereas not regulated at transcriptional level, it turned out repressed RNA levels other tropomyosins TM2 TM3, are far less T98G than Apparently, lowered TM3 affected protein heterodimer stabilization proteasomal degradation largely enhanced fibronectin/tenascin-C. This possibility supported our observation proteasome restored substratum. Our data suggest does only repress gene but also enhances their proteasome-mediated degradation. Repression TM1, suppressor-like activity, might relevant cancer, since low can protect from apoptosis. To learn more about underlying mechanism tenascin-C-induced rounding, searched for pathways, enabled spread addition, used knockdown overexpression studies together chemical inhibitors. concomittant restoration all necessary induce spreading activation endothelin receptor type B (EDNRB) induced dependent PI3K, PLC JNK, inhibitors these enzymes blocked EDNRB-induced Signaling EDNRB FAK paxillin expression, again supporting notion inactivation critical rounding. Based results (2004), described A (EDNRA) tenascin-C, know EDNRA contributes triggered upon contact 5 h. We demonstrated Collectively, responsible initial induction maintains later time points. gliomas cancers found high EDNRA, correlated advanced stages, supports potentially promotes progression EDNRA. In addition EDNRB, receptors lysophosphatidic acid (LPA) platelet-derived growth factor (PDGF) mechanism, involved paxillin, using lacking LPA/PDGF bypassed requirement Knockdown prevented LPA/PDGF-induced fibronectin/tenascin-C, suggests essential further support spreading, showed ectopic syndesmos, binds respectively. Whereas cell spreading TM2/3 observed, tightly interdependent regulation. We endothelin-1 (ET1) (EDNRB), distinct pathways. MEK, PI3K JNK. factors and, expression. Together, least (and presumably many more) mechanisms exist modulate strength combined determine migration. ET1 (through EDNRB) did trigger stimulated migration ROCK dependent. syndesmos or TM1-3, both strong as well loose These observations diagnosis may eventually allow develop novel treatments. find PDGF b correlates malignancy. Moreover, bad year survival prognosis chemotherapy response rate patients oligodendrogliomas. In summary, here anti-adhesive modulated additional factors. minimal set include Induction provides maintained same those syndecan-4.