gp130-Mediated Stat3 Activation in Enterocytes Regulates Cell Survival and Cell-Cycle Progression during Colitis-Associated Tumorigenesis
gp130-Mediated Stat3 Activation in Enterocytes Regulates Cell Survival and Cell-Cycle Progression during Colitis-Associated Tumorigenesis
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DOI：
10.1016/j.ccr.2009.01.002
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发表时间：
2009-02-03
期刊：
影响因子：
50.3
通讯作者：
Greten, Florian R.
中科院分区：
文献类型：
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作者：
Bollrath, Julia;Phesse, Toby J.;Greten, Florian R.
虽然胃肠道癌症经常与慢性炎症有关，但其潜在的分子联系尚未得到全面解释。在结肠炎相关癌症模型中使用功能丧失和获得小鼠，我们在这里建立了一个包含gp 130/Stat 3转录因子信号传导轴的链接。肠上皮细胞（IEC）特异性Stat 3消融后，突变诱导的肿瘤生长和多样性降低，而其过度活化促进肿瘤发生和生长。相反，IEC特异性Stat 3缺陷增强了对化学诱导的上皮损伤和随后的粘膜炎症的易感性，而过度的Stat 3激活赋予对结肠炎的抵抗力。Stat 3能够介导IL-6和IL-11依赖性IEC存活，并通过G1和G2/M细胞周期进程促进增殖，作为将慢性炎症与肿瘤促进联系起来的常见肿瘤细胞自主机制。
Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.