Grandis J R, Drenning S D, Chakraborty A, Zhou M Y, Zeng Q, Pitt A S, Tweardy D J
Department of Otolaryngology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
J Clin Invest. 1998 Oct 1;102(7):1385-92. doi: 10.1172/JCI3785.
Stimulation of epidermal growth factor receptor (EGFR) by ligand(s) leads to activation of signaling molecules including Stat1 and Stat3, two members of the signal transducers and activators of transcription (STAT) protein family. Activation of Stat1 and Stat3 was constitutive in transformed squamous epithelial cells, which produce elevated levels of TGF-alpha, and was enhanced by the addition of exogenous TGF-alpha. Targeting of Stat3 using antisense oligonucleotides directed against the translation initiation site, resulted in significant growth inhibition. In addition, cells stably transfected with dominant negative mutant Stat3 constructs failed to proliferate in vitro. In contrast, targeting of Stat1 using either antisense or dominant-negative strategies had no effect on cell growth. Thus, TGF-alpha/EGFR-mediated autocrine growth of transformed epithelial cells is dependent on activation of Stat3 but not Stat1.
配体对表皮生长因子受体（EGFR）的刺激会导致包括Stat1和Stat3在内的信号分子激活，Stat1和Stat3是信号转导子和转录激活子（STAT）蛋白家族的两个成员。在产生高水平转化生长因子-α（TGF-α）的转化鳞状上皮细胞中，Stat1和Stat3的激活是组成性的，并且通过添加外源性TGF-α而增强。使用针对翻译起始位点的反义寡核苷酸靶向Stat3，导致显著的生长抑制。此外，用显性负性突变Stat3构建体稳定转染的细胞在体外无法增殖。相比之下，使用反义或显性负性策略靶向Stat1对细胞生长没有影响。因此，TGF-α/EGFR介导的转化上皮细胞自分泌生长依赖于Stat3的激活而非Stat1的激活。
