Abstract
BackgroundStat3 has been classified as a proto-oncogene and constitutive Stat3 signaling appears to be involved in oncogenesis of human cancers. However, whether constitutive Stat3 signaling plays a role in the survival and growth of osteosarcomas, rhabdomyosarcomas, and soft-tissue sarcomas is still unclear.MethodsTo examine whether Stat3 is activated in osteosarcomas, rhabdomyosarcomas and other soft-tissue sarcomas we analyzed sarcoma tissue microarray slides and sarcoma cell lines using immunohistochemistry and Western blot analysis, respectively, with a phospho-specific Stat3 antibody. To examine whether the activated Stat3 pathway is important for sarcoma cell growth and survival, adenovirus-mediated expression of a dominant-negative Stat3 (Y705F) and a small molecule inhibitor (termed STA-21) were used to inhibit constitutive Stat3 signaling in human sarcoma cell lines expressing elevated levels of Stat3 phosphorylation. Cell viability was determined by MTT assays and induction of apoptosis was analyzed by western blotting using antibodies that specifically recognize cleaved caspases-3, 8, and 9.ResultsStat3 phosphorylation is elevated in 19% (21/113) of osteosarcoma, 27% (17/64) of rhabdomyosarcoma, and 15% (22/151) of other soft-tissue sarcoma tissues as well as in sarcoma cell lines. Expression of the dominant-negative Stat3 and treatment of STA-21 inhibited cell viability and growth and induced apoptosis through caspases 3, 8 and 9 pathways in human sarcoma cell lines expressing elevated levels of phosphorylated Stat3.ConclusionThis study demonstrates that Stat3 phosphorylation is elevated in human rhabdomyosarcoma, osteosarcomas and soft-tissue sarcomas. Furthermore, the activated Stat3 pathway is important for cell growth and survival of human sarcoma cells.
Highlights
Stat3 has been classified as a proto-oncogene and constitutive Stat3 signaling appears to be involved in oncogenesis of human cancers
We demonstrated that the levels of Stat3 phosphorylation is elevated in human osteosarcomas, rhabdomyosarcomas and other soft-tissue sarcomas tissues
Stat3 signaling pathway plays a role in the cell growth and survival of human sarcomas cells because our data showed that blocking constitutive Stat3 signaling in sarcoma cells induces apoptosis and growth inhibition
Summary
Stat has been classified as a proto-oncogene and constitutive Stat signaling appears to be involved in oncogenesis of human cancers. Whether constitutive Stat signaling plays a role in the survival and growth of osteosarcomas, rhabdomyosarcomas, and soft-tissue sarcomas is still unclear. The signal transducer and activator of transcription (STAT) protein family is a group of related proteins that play a role in relaying signals from cytokines and growth factors [1,2]. In a variety of human cancers, the imbalance among these signaling pathways leads to constitutive activation of Stat that is sufficient to induce cell tumorgenesis [8]. Targeting the constitutive Stat pathway has shown promise in inducing cancer cell death and restricting tumor growth [11,12,13]. Activation of Stat has become an attractive cancer therapy target [1,4]
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