Differential function of STAT5 isoforms in head and neck cancer growth control
Differential function of STAT5 isoforms in head and neck cancer growth control
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DOI：
10.1038/sj.onc.1205385
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发表时间：
2002-04-25
期刊：
影响因子：
8
通讯作者：
Grandis, JR
中科院分区：
文献类型：
--
作者：
Leong, PL;Xi, SC;Grandis, JR
表皮生长因子受体（EGFR）的上调对于多种人类癌症（包括头颈部鳞状细胞癌（SCCHN））的生长失控至关重要。EGFR的刺激导致促有丝分裂信号传导途径的激活，包括信号转导子和转录激活子（STAT）。Stat 5活化主要在造血系统恶性肿瘤中得到证实。基因破坏研究表明Stat 5亚型Stat 5a和Stat 5 b可能具有不同的功能，它们由人类17号染色体上紧密连锁的两个基因编码。为了确定Stat 5在SCCHN生长控制中的功能，我们研究了Stat 5a和Stat 5 b在正常和转化的人鳞状上皮细胞中的表达和组成性激活。与正常鳞状细胞相比，转化细胞中Stat 5的组成性激活增加。阻断TGF-α或EGFR，消除Stat 5激活。使用反义寡核苷酸靶向Stat 5 b抑制SCCHN生长。此外，SCCHN细胞稳定转染显性负突变Stat 5 b未能在体外增殖。相反，使用反义或显性负性策略靶向Stat 5a对细胞生长没有影响。这些结果表明，TGF-α/EGFR介导的转化上皮细胞的自分泌生长依赖于Stat 5 b的激活，而不是Stat 5a。
Up-regulation of the epidermal growth factor receptor (EGFR) is critical for the loss of growth control in a variety of human cancers, including squamous cell carcinoma of the head and neck (SCCHN). Stimulation of EGFR results in activation of mitogenic signaling pathways including Signal Transducers and Activators of Transcription (STATs). Stat5 activation has been primarily demonstrated in hematopoietic malignancies. Gene disruption studies suggest potentially distinct functions of the Stat5 isoforms, Stat5a and Stat5b, which are encoded by two genes closely linked on human chromosome 17. To determine the function of Stat5 in SCCHN growth control, we studied the expression and constitutive activation of Stat5a and Stat5b in normal and transformed human squamous epithelial cells. Increased constitutive activation of Stat5 was detected in transformed compared with normal squamous cells. Blockade of TGF-alpha or EGFR, abrogated Stat5 activation. Targeting of Stat5b using antisense oligonucleotides inhibited SCCHN growth. In addition, SCCHN cells stably transfected with dominant negative mutant Stat5b failed to proliferate in vitro. In contrast, targeting of Stat5a using either antisense or dominant negative strategies had no effect on cell growth. These results suggest that TGF-alpha/EGFR-mediated autocrine growth of transformed epithelial cells is dependent on activation of Stat5b but not Stat5a.