STAT-Mediated TGFalpha EGFR Signaling in squamous cell carcinoma of head neck

描述（由申请人提供）：信号转导和转录激活因子（STATs）是细胞内信号蛋白，在酪氨酸磷酸化时被激活，并从细胞质转移到细胞核，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stat3和5在头颈部鳞状细胞癌（SCCHN）中的组成性激活代表了SCCHN的关键生存途径，而Stat1的激活抑制肿瘤生长。我们最近报道，靶向Stat5b而非Stat5a可抑制体外SCCHN生长。初步研究结果表明Stat5b激活与体内SCCHN肿瘤发生有关。构成型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。在此之前，我们已经证明在SCCHN中EGFR刺激后STATs被激活。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，我们提出验证SCCHN生长控制丧失是通过获得tgf - α /EGFR自分泌信号通路介导的假设，该信号通路是由STATs的选择性激活介导的，最终目的是设计针对这些通路的新治疗策略。为了实现这一更新应用的目标，我们将：1)检查Stat5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Stat1在SCCHN中作为肿瘤抑制因子的作用机制。

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.