STAT-Mediated TGFalpha EGFR Signaling in SCCHN

描述(申请人提供)：信号转导和转录激活因子(STATs)是细胞内的信号蛋白，在酪氨酸磷酸化后被激活，并从胞浆转移到细胞核，在那里它们与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)中，STAT3和STAT5的结构性激活代表着SCCHN中的关键生存途径，而STAT1的激活则抑制肿瘤的生长。我们最近报道，靶向Stat5b，而不是Stat5a，在体外抑制了SCCHN的生长。初步研究结果表明，Stat5b的激活与SCCHN体内肿瘤的发生有关。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，我们已经证明在刺激SCCHN中的EGFR后STATS被激活。进一步的研究表明，在这些细胞中，Src家族激酶参与了EGFR/STAT的激活机制。因此，我们建议验证这样一种假设，即SCCHN中生长控制的丧失是通过获得一条由选择性激活STATS介导的转化生长因子-α/EGFR自分泌信号通路来介导的，最终目的是设计针对这些通路的新的治疗策略。为了实现这一更新应用的目标，我们将：1)检测STAT5亚型在正常和转化的黏膜鳞状上皮细胞中的不同功能；2)确定Src激酶在SCCHN中EGFR介导的STAT信号通路中的作用；以及3)确定STAT1在SCCHN中作为肿瘤抑制因子的机制。

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.