Constitutive activation of Stat5b contributes to carcinogenesis in vivo.
Constitutive activation of Stat5b contributes to carcinogenesis in vivo.
复制标题
DOI：
--
复制
发表时间：
2003-10
期刊：
影响因子：
11.2
通讯作者：
S. Xi;Qing Zhang;W. Gooding;T. Smithgall;J. Grandis
中科院分区：
文献类型：
--
作者：
S. Xi;Qing Zhang;W. Gooding;T. Smithgall;J. Grandis
对实体瘤更有效的预防和治疗策略的发展受到对致癌过程中激活的关键生长途径的不完全理解的限制。信号转导和转录激活因子（STAT）蛋白与转化和肿瘤进展有关。迄今为止的研究尚未阐明Stat 5基因（Stat 5a和Stat 5 b）在人类上皮癌中的明确和独特的作用。我们分析了Stat 5a/B亚型在头颈部鳞状细胞癌中的作用，使用选择性靶向后在人体组织和异种移植模型中的表达和活化研究。在异种移植模型中，使用反义寡核苷酸阻断Stat 5 b而非Stat 5a导致体内肿瘤生长抑制和Stat 5靶基因的消除。表皮生长因子受体的阻断导致Stat 5活化的部分消除，从而在体内将表皮生长因子受体与Stat 5连接。在来自33名头颈癌患者的组织中，Stat 5激活水平与恶性表型的进展相关，其中与上皮对应物相比，在肿瘤中检测到Stat 5 b的表达和磷酸化增加。因此，Stat 5 b的组成性激活有助于鳞状细胞肿瘤发生，并可作为治疗靶点。
The development of more effective prevention and treatment strategies for solid tumors is limited by an incomplete understanding of the critical growth pathways that are activated in carcinogenesis. Signal transducers and activators of transcription (STAT) proteins have been linked to transformation and tumor progression. Studies to date have not elucidated clear and distinct roles for Stat5genes (Stat5a and Stat5b) in human epithelial cancers. We analyzed the role of Stat5a/b isoforms in squamous cell carcinoma of the head and neck using expression and activation studies in human tissues and in a xenograft model after selective targeting. In a xenograft model, blockade of Stat5b, but not Stat5a, using antisense oligonucleotides resulted in tumor growth inhibition and abrogation of Stat5 target genes in vivo. Blockade of the epidermal growth factor receptor resulted in partial abrogation of Stat5 activation, thus linking epidermal growth factor receptor to Stat5 in vivo. In tissues from 33 individuals with head and neck cancer, Stat5 activation levels were correlated with progression to a malignant phenotype, where increased expression and phosphorylation of Stat5b were detected consistently in tumors compared with their epithelial counterparts. Thus, constitutive activation of Stat5b contributes to squamous cell tumorigenesis and may serve as a therapeutic target.