E-cadherin can limit the transforming properties of activating β-catenin mutations.
E-cadherin can limit the transforming properties of activating β-catenin mutations.
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DOI：
10.15252/embj.201591739
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发表时间：
2015-09-14
期刊：
影响因子：
--
通讯作者：
Sansom OJ
中科院分区：
文献类型：
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作者：
Huels DJ;Ridgway RA;Radulescu S;Leushacke M;Campbell AD;Biswas S;Leedham S;Serra S;Chetty R;Moreaux G;Parry L;Matthews J;Song F;Hedley A;Kalna G;Ceteci F;Reed KR;Meniel VS;Maguire A;Doyle B;Söderberg O;Barker N;Watson A;Larue L;Clarke AR;Sansom OJ
Wnt 通路失调是许多癌症的共同特征。只有结直肠癌主要存在 APC 突变，而其他癌症类型（肝细胞癌、胰腺实性假乳头状瘤）则具有 β-连环蛋白 (CTNNB1) 的激活突变。我们比较了体内 β-连环蛋白突变的动力学和效力。在小鼠小肠 (SI) 内，β-连环蛋白的激活突变需要比 Apc 或 Gsk3 损失更长的时间才能实现 Wnt 失调并获得隐窝祖细胞 (CPC) 表型。在结肠内，β-连环蛋白的单个激活突变无法驱动 Wnt 失调或诱导 CPC 表型。 β-连环蛋白突变对 SI 与结肠的这种差异转化能力与 E-钙粘蛋白的较高表达和膜上 E-钙粘蛋白：β-连环蛋白复合物的较高数量相关。 E-钙粘蛋白的减少与 β-连环蛋白的激活突变协同作用，导致 SI 和结肠内出现快速的 CPC 表型。因此，驱动转化需要 β-连环蛋白的阈值，而 E-钙粘蛋白可以充当隔离突变 β-连环蛋白的缓冲剂。
Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in β-catenin (CTNNB1). We have compared the dynamics and the potency of β-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of β-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of β-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of β-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin:β-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of β-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of β-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated β-catenin.