Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression
Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression
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DOI：
10.1002/path.5098
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发表时间：
2018-08-01
影响因子：
7.3
通讯作者：
Ishimoto, Takatsugu
中科院分区：
文献类型：
--
作者：
Eto, Tsugio;Miyake, Keisuke;Ishimoto, Takatsugu
RNF 43突变经常在结直肠癌细胞中检测到，并导致泛素E3连接酶功能丧失。在这里，我们研究了RNF 43突变在一个大型日本队列中的临床意义，以及RNF 43在结直肠癌发展和进展的各个阶段的作用。采用焦磷酸测序技术对RNF 43基因位点进行突变分析，在113例结直肠息肉病例中的1例（0.88%）和465例结直肠癌病例中的30例（6.45%）中检测到RNF 43热点突变。此外，携带突变RNF 43的结直肠癌患者的复发率高于携带非突变RNF 43的患者。此外，RNF 43沉默显著增加了RNF 43野生型结直肠癌细胞系的生长。我们通过使用CRISPR-Cas9系统在C57 BL/6 N背景中产生Rnf 43敲除小鼠。虽然来自Rnf 43敲除小鼠的肠类器官在不存在R-spondin的情况下没有显示出连续生长，但是氧化偶氮甲烷/葡聚糖硫酸钠小鼠模型证明，Rnf 43敲除小鼠中的肿瘤明显大于野生型小鼠。这些发现提供了证据，证明在肿瘤发生阶段RNF 43突变激活Wnt信号传导可增强肿瘤生长，并促进结直肠癌患者的高复发率。版权所有（C）2018大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus with pyrosequencing technology detected RNF43 hotspot mutations in one (0.88%) of 113 colorectal polyp cases and in 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knockout mice in a C57BL/6N background by using the CRISPR-Cas9 system. Although intestinal organoids from Rnf43 knockout mice did not show continuous growth in the absence of R-spondin, an azoxymethane/dextran sodium sulphate mouse model demonstrated that tumours were markedly larger in Rnf43 knockout mice than in wild-type mice. These findings provide evidence that Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer patients. Copyright (C) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.