Reduced Level of Smoothened Suppresses Intestinal Tumorigenesis by Down-Regulation of Wnt Signaling
Reduced Level of Smoothened Suppresses Intestinal Tumorigenesis by Down-Regulation of Wnt Signaling
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DOI：
10.1053/j.gastro.2009.04.059
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发表时间：
2009-08-01
期刊：
影响因子：
29.4
通讯作者：
Taketo, Makoto M.
中科院分区：
文献类型：
--
作者：
Arimura, Sumimasa;Matsunaga, Akihiro;Taketo, Makoto M.
背景与目的：尽管Hedgehog（Hh）通路调节几种类型癌症的发展和进展，但其在结肠癌中的作用仍不清楚。我们的目的是阐明Hh信号在肠道肿瘤发生中的作用。方法：我们研究了家族性腺瘤性息肉病模型Apc（+/Delta 716）小鼠肠道肿瘤中Hh信号成分的表达。我们使用针对Smoothened（SMO）的小干扰RNA（small interfering RNAs），其编码Hh通路的主要信号转导子，来敲低SMO，在人结肠癌细胞系中表达并探索其功能。我们还比较了Apc（+/Delta 716）Smo（+/-）小鼠与Apc（+/Delta 716）小鼠的肠道肿瘤表型。结果：Smo在Apc（+/Delta 716）小鼠肠腺瘤上皮中的表达明显增加。重要的是，SMO在人结肠癌细胞系中的敲低抑制了培养物中的增殖;细胞停滞在G1/S期。此外，Apc（+/Delta 716）Smo（+/-）小鼠具有减少的大尺寸类（Phi >= 1-2 mm）的息肉数量和凹陷的息肉形态，伴随着减少的肿瘤上皮细胞增殖。出乎意料的是，Smo的表达减少抑制了β-连环蛋白依赖的转录，而不是Hh响应的Gli依赖的转录。有趣的是，SMO敲除降低了活性β-连环蛋白的蛋白水平并诱导其核排斥。结论：Smo通过增加Writ信号通路促进肠道肿瘤发生。SMO可能是一个很好的治疗靶点，即使在没有Hh信号激活的情况下，大肠息肉和大肠癌患者。
BACKGROUND & AIMS: Although the Hedgehog (Hh) pathway regulates development and progression of several types of cancer, its involvement in colon cancer remains unclear. We aimed to clarify the roles of Hh signaling in intestinal tumorigenesis. METHODS: We studied expression of the Hh signaling components in the intestinal tumors of Apc(+/Delta 716) mouse, a model for familial adenomatous polyposis. We used small interfering RNAs against Smoothened (SMO), which encodes the major signal transducer of the Hh pathway, to knockdown SMO, expression and explore its function in human colon cancer cell lines. We also compared the intestinal tumor phenotypes of Apc(+/Delta 716)Smo(+/-) mice with those of Apc(+/Delta 716) mice. RESULTS: Expression of Smo was markedly increased in the intestinal adenoma epithelium of Apc(+/Delta 716) mice. Importantly, SMO knockdown in human colon cancer cell lines suppressed proliferation in culture; cells arrested at the G1/S phase. Furthermore, Apc(+/Delta 716)Smo(+/-) mice had decreased numbers of polyps in the large size class (Phi >= 1-2 mm) and recessed polyp morphology, accompanied by reduced proliferation of the tumor epithelial cells. Unexpectedly, reduced expression of Smo suppressed beta-catenin-dependent transcription, rather than Hh-responsive Gli-dependent transcription. Interestingly, SMO knockdown reduced protein levels of active beta-catenin and induced its nuclear exclusion. CONCLUSIONS: Smo contributes to intestinal tumorigenesis by increasing Writ signaling. SMO might be a good therapeutic target for patients with colorectal polyps and carcinomas, even in the absence of Hh signal activation.