Dataset Information

E-cadherin can limit the transforming properties of activating ?-catenin mutations.

ABSTRACT: 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 ?-catenin (CTNNB1). We have compared the dynamics and the potency of ?-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of ?-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 ?-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of ?-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin:?-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of ?-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of ?-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated ?-catenin.

SUBMITTER: Huels DJ

PROVIDER: S-EPMC4570519 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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E-cadherin can limit the transforming properties of activating β-catenin mutations.

Huels David J DJ Ridgway Rachel A RA Radulescu Sorina S Leushacke Marc M Campbell Andrew D AD Biswas Sujata S Leedham Simon S Serra Stefano S Chetty Runjan R Moreaux Guenievre G Parry Lee L Matthews James J Song Fei F Hedley Ann A Kalna Gabriela G Ceteci Fatih F Reed Karen R KR Meniel Valerie S VS Maguire Aoife A Doyle Brendan B Söderberg Ola O Barker Nick N Watson Alastair A Larue Lionel L Clarke Alan R AR Sansom Owen J OJ

The EMBO journal 20150803 18

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 cryp ...[more]

PMID: 26240067

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Project description:Rationale: Considerable evidence suggests that breast cancer metastasis and recurrence occur due to emergence of cancer stem cells (CSCs). In our previous study, we designed a high-throughput siRNA screening platform that identifies inflammation genes involved in the regulation of cancer cell stemness. We reported that CCL16 protein decreases OCT4 expression and reduces the ALDH+ subpopulation. However, the mechanism by which CCL16 maintains stem cell-like properties remains unclear. Methods: Tissue microarrays were used to evaluate CCL16 expression. Cancer stemness assays were performed in CCL16 knockdown and overexpressing cells in vitro and in a xenograft model in vivo. Human phosphokinase array, immunofluorescence and chromatin immunoprecipitation assays were performed to explore the underlying mechanism. Results: We report that CCL16 was overexpressed in breast tumors and significantly correlated with clinical progression. We found that silencing CCL16 in MDA-MB-231 and BT549 cells diminished CSC properties including ALDH+ subpopulation, side population, chemo-resistance, and sphere formation. Furthermore, mice bearing CCL16-silenced MDA-MB-231 xenografts had lower tumorigenic frequency and developed smaller tumors. Exploration of the underlying mechanism found that CCL16 selects CCR2 to activate p-AKT/GSK3β signaling and facilitate β-catenin nuclear translocation. Further, CCL16 binds to the OCT4 promoter and promotes OCT4 expression. In addition, shRNAs targeting CCR2 and XAV939 targeting β-catenin abolished CCL16-mediated cancer stemness. Upstream, IL10 mediates STAT3 activation, which binds to the CCL16 promoter and enhances its expression. The STAT3-targeted inhibitor Stattic suppressed CCL16 expression in vitro and restrained tumor progression in vivo. Conclusions: We identified a potential CSC regulator and suggest a novel mechanism for how CCL16 governs cancer cell stemness. We propose that CCL16 could be an effective target for breast cancer therapy.

Dataset Information

E-cadherin can limit the transforming properties of activating ?-catenin mutations.

Publications

E-cadherin can limit the transforming properties of activating β-catenin mutations.

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