Buettner Ralf, Mora Linda B, Jove Richard
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, College of Medicine, Tampa, Florida 33612, USA.
Clin Cancer Res. 2002 Apr;8(4):945-54.
The signal transducers and activators of transcription (STAT)factors function as downstream effectors of cytokine and growth factor receptor signaling. Compared with normal cells and tissues, constitutively activated STATs have been detected in a wide variety of human cancer cell lines and primary tumors. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulated process. In tumor cells, constitutive activation of STATs is linked to persistent activity of tyrosine kinases, including Src, epidermal growth factor receptor, Janus kinases, Bcr-Abl, and many others. Such oncogenic tyrosine kinases are often activated as a consequence of permanent ligand/receptor engagement in autocrine or paracrine cytokine and growth factor signaling or represent autonomous constitutively active enzymes as a result of genetic alterations found in tumor but not normal cells. Persistent signaling of specific STATs, in particular Stat3 and Stat5, has been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis. STATs participate in oncogenesis through up-regulation of genes encoding apoptosis inhibitors and cell cycle regulators such as Bcl-x(L), Mcl-1, cyclins D1/D2, and c-Myc. Inhibition of constitutively active STAT signaling pathways has been shown repeatedly to inhibit tumor cell growth in vitro and in vivo and provides a novel means for therapeutic intervention in human cancer. In this review, we will: (a) explain the mechanisms of STAT activation in normal and malignant signaling; (b) summarize recent evidence for the critical role of constitutively activated Stat3 and Stat5 in oncogenesis; (c) identify candidate STAT target genes implicated in tumor progression; and (d) discuss molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in human cancer.
信号转导与转录激活因子（STAT）作为细胞因子和生长因子受体信号传导的下游效应器发挥作用。与正常细胞和组织相比，在多种人类癌细胞系和原发性肿瘤中都检测到了组成型激活的STAT。STAT通过酪氨酸磷酸化被激活，这通常是一个短暂且受到严格调控的过程。在肿瘤细胞中，STAT的组成型激活与酪氨酸激酶的持续活性相关，这些酪氨酸激酶包括Src、表皮生长因子受体、Janus激酶、Bcr-Abl等。此类致癌性酪氨酸激酶通常是由于自分泌或旁分泌细胞因子和生长因子信号传导中配体/受体的持续结合而被激活，或者是由于肿瘤细胞而非正常细胞中发现的基因改变而成为自主组成型激活的酶。已证明特定STAT的持续信号传导，特别是Stat3和Stat5，通过刺激细胞增殖和阻止细胞凋亡直接促进肿瘤发生。STAT通过上调编码凋亡抑制剂和细胞周期调节因子的基因参与肿瘤发生，这些基因如Bcl-x(L)、Mcl-1、细胞周期蛋白D1/D2和c-Myc。反复证明抑制组成型激活的STAT信号通路可在体外和体内抑制肿瘤细胞生长，并为人类癌症的治疗干预提供了一种新方法。在本综述中，我们将：（a）解释正常和恶性信号传导中STAT激活的机制；（b）总结组成型激活的Stat3和Stat5在肿瘤发生中关键作用的最新证据；（c）确定与肿瘤进展相关的候选STAT靶基因；（d）讨论干扰STAT信号传导的分子和药理学策略，以用于人类癌症的潜在治疗干预。
