Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt-β-catenin-mediated intestinal tumor growth and regeneration
Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt-β-catenin-mediated intestinal tumor growth and regeneration
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DOI：
10.1126/scisignal.2005411
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发表时间：
2014-09-30
影响因子：
7.3
通讯作者：
Ernst, Matthias
中科院分区：
文献类型：
--
作者：
Phesse, Toby J.;Buchert, Michael;Ernst, Matthias
大多数结肠癌是由肿瘤抑制基因APC（腺瘤性结肠息肉病）的体细胞突变引起的，这些突变导致肠上皮中Wnt-至-β-连环蛋白途径的组成性激活。由于Wnt-β-连环蛋白信号传导是成体肠上皮细胞的稳态和再生所必需的，因此该途径的治疗靶向是具有挑战性的。我们发现，由受体gp 130，相关的Jak（Janus激酶）激酶和转录因子Stat 3（信号转导和转录激活因子3）介导的精氨酸刺激途径的遗传激活是野生型小鼠辐射诱导损伤的肠道再生和APC突变小鼠肿瘤发生所需的。gp 130-Jak-Stat 3信号传导的全身药理学或部分遗传抑制抑制了肠再生、APC突变小鼠中的肿瘤生长以及结肠癌异种移植物的生长。Apc突变型肿瘤的生长依赖于gp 130-Jak-Stat 3信号传导，用于诱导多梳型阻遏物Bmi-1，以及相关的细胞周期抑制剂p16和p21编码基因的阻遏。然而，抑制gp 130-Jak-Stat 3信号传导并不影响Wnt-b-catenin信号传导或肠内稳态。因此，这些数据不仅表明了gp 130-Jak-Stat 3通路如何促进癌症的分子机制，而且还为结肠癌中Jak的治疗性抑制提供了理论基础。
Most colon cancers arise from somatic mutations in the tumor suppressor gene APC (adenomatous polyposis coli), and these mutations cause constitutive activation of the Wnt-to-beta-catenin pathway in the intestinal epithelium. Because Wnt-beta-catenin signaling is required for homeostasis and regeneration of the adult intestinal epithelium, therapeutic targeting of this pathway is challenging. We found that genetic activation of the cytokine-stimulated pathway mediated by the receptor gp130, the associated Jak (Janus kinase) kinases, and the transcription factor Stat3 (signal transducer and activator of transcription 3) was required for intestinal regeneration in response to irradiation-induced damage in wild-type mice and for tumorigenesis in Apc-mutant mice. Systemic pharmacological or partial genetic inhibition of gp130-Jak-Stat3 signaling suppressed intestinal regeneration, the growth of tumors in Apc-mutant mice, and the growth of colon cancer xenografts. The growth of Apc-mutant tumors depended on gp130-Jak-Stat3 signaling for induction of the polycomb repressor Bmi-1, and the associated repression of genes encoding the cell cycle inhibitors p16 and p21. However, suppression of gp130-Jak-Stat3 signaling did not affect Wnt-b-catenin signaling or homeostasis in the intestine. Thus, these data not only suggest a molecular mechanism for how the gp130-Jak-Stat3 pathway can promote cancer but also provide a rationale for therapeutic inhibition of Jak in colon cancer.