Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo
Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo
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DOI：
10.1073/pnas.97.8.4227
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发表时间：
2000-04-11
影响因子：
11.1
通讯作者：
Kim, JD
中科院分区：
文献类型：
--
作者：
Grandis, JR;Drenning, SD;Kim, JD
当暴露在环境致癌物中时，大田癌变使上呼吸道粘膜易于形成多原发肿瘤。表皮生长因子受体的上调发生在鳞状细胞癌的早期，在包括头颈部鳞状细胞癌在内的各种人类癌症中，表皮生长因子受体的上调是失去生长控制的关键。在这些培养的肿瘤细胞中，表皮生长因子受体刺激通过选择性STAT蛋白的持续激活来启动信号转导。为了确定STAT3在头颈部癌变过程中的激活时间，我们研究了STAT3在头颈癌患者肿瘤和正常黏膜中的表达及结构性激活，并与正常对照进行了比较。STAT3在头颈部原发肿瘤及癌旁正常粘膜中表达上调，并呈结构性激活，与非癌对照正常粘膜相比。在头颈部异种移植模型中，脂质体介导的STAT3反义基因治疗有效地抑制了STAT3的激活，增加了肿瘤细胞的凋亡，并降低了Bclx(L)的表达。这些发现提供了证据，即结构性激活的STAT3是头颈部癌变的早期事件，有助于通过抗凋亡机制失去对生长的控制。
Field cancerization predisposes the upper aerodigestive tract mucosa to the formation of multiple primary tumors, when exposed to environmental carcinogens. Up-regulation of epidermal growth factor receptor occurs early in squamous cell carcinogenesis and is critical for the loss of growth control in a variety of human cancers, including head and neck squamous cell carcinomas. In these tumor cells in culture, epidermal growth factor receptor stimulation initiates signaling via persistent activation of selective STAT proteins. To determine the timing of Stat3 activation in head and neck carcinogenesis, we studied the expression and constitutive activation of Stat3 in tumors and normal mucosa from patients with head and neck cancer compared with mucosa from controls without cancer. Stat3 was up-regulated and constitutively activated in both primary human head and neck tumors as well as in normal mucosa from these cancer patients compared with control normal mucosa from patients without cancer. In vivo liposome-mediated gene therapy with a Stat3 antisense plasmid efficiently inhibited Stat3 activation, increased tumor cell apoptosis, and decreased Bcl-x(L) expression in a head and neck xenograft model. These findings provide evidence that constitutively activated Stat3 is an early event in head and neck carcinogenesis that contributes to the loss of growth control by an anti-apoptotic mechanism.