New and old functions of STAT3 - A pivotal target for individualized treatment of cancer
New and old functions of STAT3 - A pivotal target for individualized treatment of cancer
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DOI：
10.4161/cc.4.9.1985
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发表时间：
2005-09-01
期刊：
影响因子：
4.3
通讯作者：
Levy, DE
中科院分区：
文献类型：
--
作者：
Inghirami, G;Chiarle, R;Levy, DE
信号转导和转录激活因子（STAT）调节过多的细胞因子反应。最近，STAT蛋白的异常信号传导已被证明在许多肿瘤的发病机制中发挥重要作用，通过促进细胞周期进展和存活，刺激血管生成，损害免疫反应和肿瘤监测。我们已经开发了遗传工具来评估STAT3依赖性恶性肿瘤，并表明淋巴样恶性肿瘤的生存和生长需要STAT3的表达。相反，正常细胞中STAT3的缺失并不影响其生长或存活；但是，尽管STAT3具有这种明显的可有可无的作用，但STAT3缺失的成纤维细胞对多种癌基因的转化具有抗性。STAT3致瘤活性的精确分子机制仅被部分阐明。虽然STAT3的酪氨酸磷酸化（表明其信号依赖性激活）在肿瘤中很常见，并且在一些恶性肿瘤中似乎起着至关重要的作用，但各种新数据表明，在某些情况下，它可能是可缺性的，STAT3可以通过新的和非规范的机制参与转化。STAT3作用的非规范模式的发现和解剖将为设计能够中和该分子致瘤特性的有效治疗方法开辟新的途径。
Signal transducers and activators of transcription ( STAT) regulate a plethora of cytokine responses. Recently, aberrant signaling by STAT proteins has been demonstrated to play important roles in the pathogenesis of many neoplasms, by promoting cell cycle progression and survival, stimulating angiogenesis, and impairing immunological responses and tumor surveillance. We have developed genetic tools to evaluate STAT-dependent malignancy and showed that survival and growth of lymphoid malignancies requires expression of STAT3. In contrast, loss of STAT3 in normal cells does not impair their growth or survival; but in spite of this apparent dispensability of STAT3, STAT3-null fibroblasts are resistant to transformation by a variety of oncogenes. The precise molecular mechanisms responsible for the tumorigenic activity of STAT3 have been only partially elucidated. While the tyrosine phosphorylation of STAT3, which is indicative of its signal-dependent activation, is a common occurrence in tumors, and appears to play a crucial role in some malignancies, a variety of new data suggest that it can be dispensable under some circumstances and STAT3 can participate in transformation through novel and non-canonical mechanisms. The discovery and dissection of non-canonical modes of STAT3 action will open new avenues for the design of effective therapeutics capable of neutralizing the tumorigenic properties of this molecule.