STAT-Mediated TGFalpha EGFR Signaling in SCCHN

描述（由申请人提供）：信号转导和转录激活因子（STAT）是细胞内信号传导蛋白，其在酪氨酸磷酸化后被激活，并从细胞溶质易位到细胞核，在细胞核中它们与DNA的特定区域结合并发挥转录活性。我们已经积累了令人信服的证据表明，在头颈部鳞状细胞癌（SCCHN）的组成性激活STATs 3和5代表SCCHN的关键生存途径，而Stat 1激活抑制肿瘤生长。我们最近报道，靶向Stat 5 b，而不是Stat 5a，废除SCCHN生长在体外。初步研究结果表明，Stat 5 b激活与体内SCCHN肿瘤发生有关。组成性STAT激活的潜在原因包括上游受体和非受体激酶的自分泌刺激。以前，我们已经表明，STATs被激活后，EGFR在SCCHN的刺激。进一步的研究表明Src家族激酶参与了这些细胞中EGFR/STAT的激活机制。因此，我们建议测试这一假设，即在SCCHN的生长控制的损失是通过收购介导的TGF-α/EGFR自分泌信号通路，是由选择性激活的STAT介导的，与设计新的治疗策略，以这些途径的最终目的。为了实现这一更新申请的目标，我们将：1）检查Stat 5亚型在正常和转化的粘膜鳞状上皮细胞中的差异功能; 2）确定Src激酶在SCCHN中EGFR介导的STAT信号通路中的作用; 3）确定Stat 1在SCCHN中作为肿瘤抑制因子发挥作用的机制。

DESCRIPTION (provided by applicant): Signal Transducers and Activators of Transcription (STATs) are intracellular signaling proteins that are activated upon tyrosine phosphorylation and translocate from the cytosol to the nucleus where they bind to specific regions of DNA and exert transcriptional activity. We have accumulated convincing evidence that constitutive activation of STATs 3 and 5 in squamous cell carcinoma of the head and neck (SCCHN) represent critical survival pathways in SCCHN, whereas Stat1 activation inhibits tumor growth. We recently reported that targeting Stat5b, but not Stat5a, abrogated SCCHN growth in vitro. Results of preliminary studies demonstrate that Stat5b activation is linked to SCCHN tumorigenesis in vivo. Potential causes of constitutive STAT activation include autocrine stimulation of upstream receptor and non-receptor kinases. Previously, we have shown that STATs are activated following stimulation of EGFR in SCCHN. Further investigation implicates Src family kinases in EGFR/STAT activation mechanisms in these cells. Therefore, we propose to test the hypothesis that loss of growth control in SCCHN is mediated through acquisition of a TGF-alpha/EGFR autocrine signaling pathway that is mediated by selective activation of STATs, with the ultimate aim of designing novel treatment strategies to target these pathways. To accomplish the goals of this renewal application, we will: 1) examine the differential function of Stat5 isoforms in normal and transformed mucosal squamous epithelial cells; 2) determine the role of Src kinases in EGFR-mediated STAT signaling pathways in SCCHN; and 3) determine the mechanisms by which Stat1 functions as a tumor suppressor in SCCHN.