Severe polyposis in Apc(1322T) mice is associated with submaximal Wnt signalling and increased expression of the stem cell marker Lgr5.
Severe polyposis in Apc(1322T) mice is associated with submaximal Wnt signalling and increased expression of the stem cell marker Lgr5.
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DOI：
10.1136/gut.2009.193680
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发表时间：
2010-12
期刊：
影响因子：
24.5
通讯作者：
Tomlinson I
中科院分区：
文献类型：
--
作者：
Lewis A;Segditsas S;Deheragoda M;Pollard P;Jeffery R;Nye E;Lockstone H;Davis H;Clark S;Stamp G;Poulsom R;Wright N;Tomlinson I
大肠腺瘤性息肉病(APC)是一种肿瘤抑制基因，在家族性腺瘤性息肉病(FAP)患者的胚系中发生突变，在大多数结直肠癌中也存在体细胞突变。APC突变削弱了β-连环蛋白的降解，导致Wnt信号的增加。最常见的APC突变是与严重FAP相关的1309密码子截断。先前的一项研究比较了两种肠道肿瘤发生的小鼠模型，ApcR850X(Min)和Apc1322T(1322T)，后者是人类密码子1309变化的模型。1322T小鼠患有更严重的息肉病，但令人惊讶的是，这些肿瘤的核β-连环蛋白水平低于MIN肿瘤。研究了这些不同的β-连环蛋白水平的后果。用显微切割法从1322T和Min肿瘤中分离肠上皮细胞，并进行基因表达谱分析。采用定量聚合酶链式反应、原位杂交和免疫组织化学方法对差异表达的Wnt靶点和其他干细胞标志物进行验证。正如预期的那样，在1322T病变中，较低的核β-连环蛋白水平与一般较低的WNT靶标表达水平相关。然而，Wnt靶标和干细胞标记物Lgr5在1322T肿瘤中的表达显著高于Min肿瘤。其他干细胞标记物(Musashi1、Bmi1和Wnt靶标CD44)在1322T肿瘤中也处于较高水平。此外，BMP拮抗剂Gremlin1在1322T肿瘤中的表达较高，而BMP2和Bmp4的表达较低。APC在1322密码子截短导致的严重表型与干细胞数量的增加有关。因此，低于最大水平的Wnt信号有利于干细胞表型，这可能会促进肿瘤的发生。对于肿瘤的最佳生长来说，Wnt信号的水平太高了。
Adenomatous polyposis coli (APC) is a tumour suppressor gene mutated in the germline of patients with familial adenomatous polyposis (FAP) and somatically in most colorectal cancers. APC mutations impair β-catenin degradation, resulting in increased Wnt signalling. The most frequent APC mutation is a codon 1309 truncation that is associated with severe FAP. A previous study compared two mouse models of intestinal tumorigenesis, ApcR850X (Min) and Apc1322T (1322T), the latter a model of human codon 1309 changes. 1322T mice had more severe polyposis but, surprisingly, these tumours had lower levels of nuclear β-catenin than Min tumours. The consequences of these different β-catenin levels were investigated. Enterocytes were isolated from 1322T and Min tumours by microdissection and gene expression profiling was performed. Differentially expressed Wnt targets and other stem cell markers were validated using quantitative PCR, in situ hybridisation and immunohistochemistry. As expected, lower nuclear β-catenin levels in 1322T lesions were associated with generally lower levels of Wnt target expression. However, expression of the Wnt target and stem cell marker Lgr5 was significantly higher in 1322T tumours than in Min tumours. Other stem cell markers (Musashi1, Bmi1 and the Wnt target Cd44) were also at higher levels in 1322T tumours. In addition, expression of the Bmp antagonist Gremlin1 was higher in 1322T tumours, together with lower Bmp2 and Bmp4 expression. The severe phenotype caused by truncation of Apc at codon 1322 is associated with an increased number of stem cells. Thus, a submaximal level of Wnt signalling favours the stem cell phenotype and this may promote tumorigenesis. A level of Wnt signalling exists that is too high for optimal tumour growth.
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影响因子：
30.8
作者：
Sangiorgi, Eugenio;Capecchi, Mario R.
通讯作者：
Capecchi, Mario R.
影响因子：
2
作者：
Loeffler, M;Bratke, T;Potten, CS
通讯作者：
Potten, CS
影响因子：
5.3
作者：
Morita, H;Mazerbourg, S;Hsueh, AJW
通讯作者：
Hsueh, AJW
影响因子：
64.8
作者：
Sansom, Owen J.;Meniel, Valerie S.;Clarke, Alan R.
通讯作者：
Clarke, Alan R.
DOI：
10.1385/scr:1:3:233
发表时间：
2005-01-01
期刊：
STEM CELL REVIEWS
影响因子：
--
作者：
Leedham, S. J.;Thliveris, A. T.;Wright, N. A.
通讯作者：
Wright, N. A.