期刊
EMBO JOURNAL
卷 34, 期 18, 页码 2321-2333出版社
WILEY
DOI: 10.15252/embj.201591739
关键词
APC; beta-catenin; colorectal cancer; E-cadherin
资金
- Cancer Research UK [C596/A17196]
- European Union [278568]
- North West Cancer Research Fund [CR700]
- ERC
- Biotechnology and Biological Sciences Research Council [BBS/E/F/00044446] Funding Source: researchfish
- Cancer Research UK [16581, 22311] Funding Source: researchfish
- Medical Research Council [MR/K000063/1, MR/L016508/1] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [21139] Funding Source: researchfish
- BBSRC [BBS/E/F/00044446] Funding Source: UKRI
- MRC [MR/K000063/1, MR/L016508/1] Funding Source: UKRI
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 beta-catenin (CTNNB1). We have compared the dynamics and the potency of beta-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of beta-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 beta-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of beta-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin: beta-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of beta-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of beta-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated beta-catenin.
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